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Entry
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- *156845 - MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTOR; MITF
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<li class="dropdown-header">
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<a href="/history"> Search History </a>
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</form>
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<p />
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</div>
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*156845</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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="#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/156845">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000187098;t=ENST00000352241" 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=4286" 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=156845" 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=ENSG00000187098;t=ENST00000352241" 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_000248,NM_001184967,NM_001184968,NM_001354604,NM_001354605,NM_001354606,NM_001354607,NM_001354608,NM_006722,NM_198158,NM_198159,NM_198177,NM_198178" 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_001354604" 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=156845" 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=01138&isoform_id=01138_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/MITF" 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/468497,3413847,4557755,5817113,7684294,7684299,7684301,7684303,13124344,18249647,18700304,20071597,24024987,38156697,38156699,38156701,38156703,40807040,119585883,119585884,119585885,119585886,119585887,119585888,158256072,194382238,194388442,284484546,296841085,296841087,296923804,733387121,918027005,1001946530,1231802355,1231802365,1231802370,1231802428,1237937630,2076079957,2076079963" 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/O75030" 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=4286" 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=ENSG00000187098;t=ENST00000352241" 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=MITF" 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=MITF" 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+4286" 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/MITF" 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:4286" 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/4286" 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=chr3&hgg_gene=ENST00000352241.9&hgg_start=69739464&hgg_end=69968332&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:7105" 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:7105" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=156845[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=156845[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/MITF/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/ENSG00000187098" 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=MITF" 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=MITF" 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=MITF" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/MITF" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MITF&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/PA30823" 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:7105" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0263112.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:104554" 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/MITF#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:104554" 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/4286/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=000214,000915,001401,001680,001931,002629,002679,002764,002795" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4286" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00020930;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-010919-1" 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:4286" 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=MITF&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> 1332382002, 403805009<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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156845
|
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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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MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTOR; MITF
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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MICROPHTHALMIA, MOUSE, HOMOLOG OF; MI
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MITF" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MITF</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/3/454?start=-3&limit=10&highlight=454">3p13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:69739464-69968332&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'})">3:69,739,464-69,968,332</a> </span>
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{Melanoma, cutaneous malignant, susceptibility to, 8}
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COMMAD syndrome
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Tietz albinism-deafness syndrome
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PheneGene Graphics <span class="caret"></span>
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</button>
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<li><a href="/graph/linear/156845" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/156845" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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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>MITF is a basic helix-loop-helix (hHLH)-leucine zipper protein that plays a role in the development of various cell types, including neural crest-derived melanocytes and optic cup-derived retinal pigment epithelial cells (<a href="#9" class="mim-tip-reference" title="Fuse, N., Yasumoto, K., Takeda, K., Amae, S., Yoshizawa, M., Udono, T., Takahashi, K., Tamai, M., Tomita, Y., Tachibana, M., Shibahara, S. <strong>Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus.</strong> J. Biochem. 126: 1043-1051, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10578055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10578055</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a022548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10578055">Fuse et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10578055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The mouse 'microphthalmia' (mi) gene encodes a bHLH zipper protein that functions as a homodimeric transcription factor. Mutations in mi lead to loss of pigmentation in the eye, inner ear, and skin, and to reduced eye size and early-onset deafness. Mice with mi mutations serve as models for human pigment disturbances in skin and eye that may be combined with sensorineural deafness. <a href="#32" class="mim-tip-reference" title="Tachibana, M., Perez-Jurado, L. A., Nakayama, A., Hodgkinson, C. A., Li, X., Schneider, M., Miki, T., Fex, J., Francke, U., Arnheiter, H. <strong>Cloning of MITF, the human homolog of the mouse microphthalmia gene and assignment to chromosome 3p14.1-p12.3.</strong> Hum. Molec. Genet. 3: 553-557, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069297</a>] [<a href="https://doi.org/10.1093/hmg/3.4.553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069297">Tachibana et al. (1994)</a> obtained cDNA and genomic clones of the human homolog of mouse mi, MITF, and identified a restriction fragment length polymorphism in the gene. The deduced mouse and human MITF proteins share 94.3% amino acid identity. Both proteins contain 419 amino acids and have central bHLH domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Fuse, N., Yasumoto, K., Takeda, K., Amae, S., Yoshizawa, M., Udono, T., Takahashi, K., Tamai, M., Tomita, Y., Tachibana, M., Shibahara, S. <strong>Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus.</strong> J. Biochem. 126: 1043-1051, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10578055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10578055</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a022548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10578055">Fuse et al. (1999)</a> noted that 3 different MITF splice variants, MITF-A, MITF-M, and MITF-H, had been identified. The variants differ in their 5-prime ends and encode proteins with different N termini. The deduced MITF-A, MITF-H, and MITF-M proteins have calculated molecular masses of 58.2, 56.4, and 46.9 kD, respectively. All MITF isoforms have a central transcriptional activation domain, followed by a bHLH-leucine zipper region and a C-terminal serine-rich region. MITF-M differs from the other isoforms in that it has a 6-amino acid insertion prior to the basic region. <a href="#9" class="mim-tip-reference" title="Fuse, N., Yasumoto, K., Takeda, K., Amae, S., Yoshizawa, M., Udono, T., Takahashi, K., Tamai, M., Tomita, Y., Tachibana, M., Shibahara, S. <strong>Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus.</strong> J. Biochem. 126: 1043-1051, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10578055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10578055</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a022548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10578055">Fuse et al. (1999)</a> cloned a novel MITF splice variant, MITF-C, by PCR and 5-prime RACE of a kidney cDNA library. The deduced MITF-C protein contains 519 amino acids and has a calculated molecular mass of 58.0 kD. Like the other MITF isoforms, MITF-C has a unique N terminus, and it does not have the 6-amino acid insertion found in MITF-M. RT-PCR detected coexpression of MITF-A and MITF-H in all human cell lines examined and in kidney, whereas MITF-M was detected only in melanoma cell lines. MITF-C was expressed in many cell lines, but not in melanomas. Western blot analysis of HeLa cells transfected with these 4 MITF variants revealed proteins that migrated at apparent molecular masses higher than their calculated molecular masses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10578055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Udono, T., Yasumoto, K., Takeda, K., Amae, S., Watanabe, K., Saito, H., Fuse, N., Tachibana, M., Takahashi, K., Tamai, M., Shibahara, S. <strong>Structural organization of the human microphthalmia-associated transcription factor gene containing four alternative promoters.</strong> Biochim. Biophys. Acta 1491: 205-219, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10760582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10760582</a>] [<a href="https://doi.org/10.1016/s0167-4781(00)00051-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10760582">Udono et al. (2000)</a> identified a novel MITF splice variant, MITF-B, that encodes a 495-amino acid protein with a calculated molecular mass of 55.4 kD. RT-PCR detected MITF-B expression in all cell types examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10760582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>As mice with mutations at mi alleles and humans with WS2 lack melanocytes in affected tissues, <a href="#33" class="mim-tip-reference" title="Tachibana, M., Takeda, K., Nobukuni, Y., Urabe, K., Long, J. E., Meyers, K. A., Aaronson, S. A., Miki, T. <strong>Ectopic expression of MITF, a gene for Waardenburg syndrome type 2, converts fibroblasts to cells with melanocytes characteristics.</strong> Nature Genet. 14: 50-54, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782819</a>] [<a href="https://doi.org/10.1038/ng0996-50" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782819">Tachibana et al. (1996)</a> speculated that MITF may be involved in mediating melanocyte differentiation by functioning as a transcription factor. In support of this idea, they demonstrated that NIH 3T3 cells transfected with MITF developed melanocytic phenotypes. MITF transfectants formed foci of morphologically altered cells, which resembled those induced by oncogenes, but did not exhibit malignant phenotypes. Instead, they contained dendritic cells that expressed melanogenic marker proteins such as tyrosinase and tyrosinase-related protein-1 (TYRP1; <a href="/entry/115501">115501</a>). Such properties were not observed in cells transfected with the closely related TFE3 cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mutations in MITF and PAX3, encoding transcription factors, are responsible for Waardenburg syndrome type 2A (WS2A; <a href="/entry/193510">193510</a>) and WS1/WS3 (<a href="/entry/193500">193500</a>, <a href="/entry/148820">148820</a>), respectively. <a href="#33" class="mim-tip-reference" title="Tachibana, M., Takeda, K., Nobukuni, Y., Urabe, K., Long, J. E., Meyers, K. A., Aaronson, S. A., Miki, T. <strong>Ectopic expression of MITF, a gene for Waardenburg syndrome type 2, converts fibroblasts to cells with melanocytes characteristics.</strong> Nature Genet. 14: 50-54, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782819</a>] [<a href="https://doi.org/10.1038/ng0996-50" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782819">Tachibana et al. (1996)</a> showed that MITF transactivates the gene for tyrosinase (TYR; <a href="/entry/606933">606933</a>), a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation in the skin, hair, and eyes, and hearing function in the cochlea. Therefore, hypopigmentation and hearing loss in WS2 are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations. However, the molecular mechanism by which PAX3 mutations cause the auditory-pigmentary symptoms in WS1/WS3 had not been explained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Watanabe, A., Takeda, K., Ploplis, B., Tachibana, M. <strong>Epistatic relationship between Waardenburg syndrome genes MITF and PAX3.</strong> Nature Genet. 18: 283-286, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9500554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9500554</a>] [<a href="https://doi.org/10.1038/ng0398-283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9500554">Watanabe et al. (1998)</a> showed that PAX3, a transcription factor with a paired domain and a homeodomain, transactivates the MITF promoter. They further showed that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain failed to recognize and transactivate the MITF promoter. These results provided evidence that PAX3 directly regulates MITF, and suggested that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9500554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mouse follicular melanocytes, production of eumelanins and pheomelanins is under the control of 2 intercellular signaling molecules that exert opposite actions: alpha-MSH (see <a href="/entry/176830">176830</a>), which preferentially increases the synthesis of eumelanins, and agouti signal protein (ASP; <a href="/entry/600201">600201</a>), whose expression favors the production of hair containing pheomelanins. <a href="#1" class="mim-tip-reference" title="Aberdam, E., Bertolotto, C., Sviderskaya, E. V., de Thillot, V., Hemesath, T. J., Fisher, D. E., Bennett, D. C., Ortonne, J.-P., Ballotti, R. <strong>Involvement of microphthalmia in the inhibition of melanocyte lineage differentiation and of melanogenesis by agouti signal protein.</strong> J. Biol. Chem. 273: 19560-19565, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9677380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9677380</a>] [<a href="https://doi.org/10.1074/jbc.273.31.19560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9677380">Aberdam et al. (1998)</a> reported that ASP not only affects mature melanocytes but can also inhibit the differentiation of melanoblasts. They showed that both alpha-MSH and forskolin promote the differentiation of murine melanoblasts into mature melanocytes, and that ASP inhibits this process. Expression of MITF and its binding to an M-box regulatory element is inhibited by ASP. <a href="#1" class="mim-tip-reference" title="Aberdam, E., Bertolotto, C., Sviderskaya, E. V., de Thillot, V., Hemesath, T. J., Fisher, D. E., Bennett, D. C., Ortonne, J.-P., Ballotti, R. <strong>Involvement of microphthalmia in the inhibition of melanocyte lineage differentiation and of melanogenesis by agouti signal protein.</strong> J. Biol. Chem. 273: 19560-19565, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9677380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9677380</a>] [<a href="https://doi.org/10.1074/jbc.273.31.19560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9677380">Aberdam et al. (1998)</a> also showed that in a murine melanoma cell line, ASP inhibits alpha-MSH-stimulated expression of tyrosinase (see <a href="/entry/606933">606933</a>), TYRP1, and TYRP2 (DCT; <a href="/entry/191275">191275</a>) through an inhibition of the transcriptional activity of their respective promoters. Further, ASP inhibits alpha-MSH-induced expression of the MITF gene and reduces the level of MITF in the cells. <a href="#1" class="mim-tip-reference" title="Aberdam, E., Bertolotto, C., Sviderskaya, E. V., de Thillot, V., Hemesath, T. J., Fisher, D. E., Bennett, D. C., Ortonne, J.-P., Ballotti, R. <strong>Involvement of microphthalmia in the inhibition of melanocyte lineage differentiation and of melanogenesis by agouti signal protein.</strong> J. Biol. Chem. 273: 19560-19565, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9677380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9677380</a>] [<a href="https://doi.org/10.1074/jbc.273.31.19560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9677380">Aberdam et al. (1998)</a> concluded that ASP can regulate both melanoblast differentiation and melanogenesis, pointing out the key role of MITF in the control of these processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9677380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Fuse, N., Yasumoto, K., Takeda, K., Amae, S., Yoshizawa, M., Udono, T., Takahashi, K., Tamai, M., Tomita, Y., Tachibana, M., Shibahara, S. <strong>Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus.</strong> J. Biochem. 126: 1043-1051, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10578055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10578055</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a022548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10578055">Fuse et al. (1999)</a> found that MITF-A, MITF-H, MITF-M, and MITF-C transactivated a tyrosinase test promoter in transfected HeLa cells. All tested isoforms, except MITF-C, also weakly transactivated a heme oxygenase-1 (HMOX1; <a href="/entry/141250">141250</a>) test promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10578055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Udono, T., Yasumoto, K., Takeda, K., Amae, S., Watanabe, K., Saito, H., Fuse, N., Tachibana, M., Takahashi, K., Tamai, M., Shibahara, S. <strong>Structural organization of the human microphthalmia-associated transcription factor gene containing four alternative promoters.</strong> Biochim. Biophys. Acta 1491: 205-219, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10760582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10760582</a>] [<a href="https://doi.org/10.1016/s0167-4781(00)00051-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10760582">Udono et al. (2000)</a> showed that MITF-B transactivated the tyrosinase, TYRP1, and TYRP2 promoters. The ability of MITF-A, MITF-H, and MITF-M to transactivate promoter activity varied depending on the cell types assayed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10760582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#34" class="mim-tip-reference" title="Takeda, K., Takemoto, C., Kobayashi, I., Watanabe, A., Nobukuni, Y., Fisher, D. E., Tachibana, M. <strong>Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance.</strong> Hum. Molec. Genet. 9: 125-132, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587587</a>] [<a href="https://doi.org/10.1093/hmg/9.1.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587587">Takeda et al. (2000)</a> demonstrated that serine at codon 298 plays an important role in MITF function. Glycogen synthase kinase-3B (GSK3B; <a href="/entry/605004">605004</a>) was found to phosphorylate serine-298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter. Serine-298 was also phosphorylated in vivo, and expression of dominant-negative GSK3-beta selectively suppressed the ability of MITF to transactivate the tyrosinase promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Khaled, M., Larribere, L., Bille, K., Aberdam, E., Ortonne, J.-P., Ballotti, R., Bertolotto, C. <strong>Glycogen synthase kinase 3-beta is activated by cAMP and plays an active role in the regulation of melanogenesis.</strong> J. Biol. Chem. 277: 33690-33697, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093801</a>] [<a href="https://doi.org/10.1074/jbc.M202939200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093801">Khaled et al. (2002)</a> found that GSK3B synergized with MITF in mouse melanoma cells to activate the tyrosinase promoter. Lithium, a GSK3B inhibitor, impaired the response of the tyrosinase promoter to cAMP, and cAMP increased binding of MITF to the M-box regulatory element. <a href="#15" class="mim-tip-reference" title="Khaled, M., Larribere, L., Bille, K., Aberdam, E., Ortonne, J.-P., Ballotti, R., Bertolotto, C. <strong>Glycogen synthase kinase 3-beta is activated by cAMP and plays an active role in the regulation of melanogenesis.</strong> J. Biol. Chem. 277: 33690-33697, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093801</a>] [<a href="https://doi.org/10.1074/jbc.M202939200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093801">Khaled et al. (2002)</a> concluded that activation of GSK3B by cAMP facilitates MITF binding to the tyrosinase promoter, stimulating melanogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12093801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M. <strong>Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.</strong> Hum. Molec. Genet. 9: 1907-1917, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942418</a>] [<a href="https://doi.org/10.1093/hmg/9.13.1907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10942418">Bondurand et al. (2000)</a> showed that SOX10 (<a href="/entry/602229">602229</a>), in synergy with PAX3, strongly activates MITF expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in WS could explain the auditory/pigmentary symptoms of this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 SOX10 and PAX3 transcription factors can directly regulate both MITF and RET in a synergistic fashion. <a href="#17" class="mim-tip-reference" title="Lang, D., Epstein, J. A. <strong>Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer.</strong> Hum. Molec. Genet. 12: 937-945, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668617</a>] [<a href="https://doi.org/10.1093/hmg/ddg107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668617">Lang and Epstein (2003)</a> showed that PAX3 and SOX10 can physically interact; this interaction contributes to synergistic activation of a conserved RET enhancer, and it explains why SOX10 mutants that cannot bind DNA still retain the ability to activate this enhancer in the presence of PAX3. However, in the context of the MITF gene, PAX3 and SOX10 must each bind independently to DNA in order to achieve synergy. These observations appear to explain the Waardenburg syndrome type 2E phenotype (WS2E; <a href="/entry/611584">611584</a>) caused by a specific SOX10 mutation (<a href="/entry/602229#0005">602229.0005</a>) in the HMG box that abrogates DNA binding without disrupting association with PAX3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>There is a phenotypic similarity between microphthalmia Mitf mi/mi mutant mice and cathepsin K (<a href="/entry/601105">601105</a>)-null mice as well as the human disease pycnodysostosis (<a href="/entry/265800">265800</a>) caused by cathepsin K deficiency. Cathepsin K is a cysteine protease from the papain family of proteases and plays an important role in osteoclast function. In mice, dominant-negative, but not recessive, mutations of Mitf produce osteopetrosis (see <a href="/entry/166600">166600</a>), suggesting a functional requirement for other family members, such as TFE3 (<a href="/entry/314310">314310</a>), TFEB (<a href="/entry/600744">600744</a>), and TFEC (<a href="/entry/604732">604732</a>), which are potential dimerization partners. <a href="#23" class="mim-tip-reference" title="Motyckova, G., Weilbaecher, K. N., Horstmann, M., Rieman, D. J., Fisher, D. Z., Fisher, D. E. <strong>Linking osteopetrosis and pycnodysostosis: regulation of cathepsin K expression by the microphthalmia transcription factor family.</strong> Proc. Nat. Acad. Sci. 98: 5798-5803, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331755</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11331755[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.091479298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11331755">Motyckova et al. (2001)</a> identified cathepsin K as a transcriptional target of MITF and TFE3 (<a href="/entry/314310">314310</a>) via 3 consensus elements in the cathepsin K promoter. Additionally, cathepsin K mRNA and protein were found to be deficient in Mitf mutant osteoclasts, and overexpression of wildtype Mitf dramatically upregulated the expression of endogenous cathepsin K in cultured human osteoclasts. Cathepsin K promoter activity was disrupted by dominant-negative, but not recessive, mouse alleles of Mitf in a pattern that closely matches their osteopetrotic phenotypes. This relationship between cathepsin K and the MITF family helps explain the phenotypic overlap of their corresponding deficiencies in pycnodysostosis and osteopetrosis and identifies likely regulators of cathepsin K expression in bone homeostasis and human malignancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11331755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify MITF-dependent KIT (<a href="/entry/164920">164920</a>) transcriptional targets in primary human melanocytes, microarray studies were undertaken by <a href="#20" class="mim-tip-reference" title="McGill, G. G., Horstmann, M., Widlund, H. R., Du, J., Motyckova, G., Nishimura, E. K., Lin, Y.-L., Ramaswamy, S., Avery, W., Ding, H.-F., Jordan, S. A., Jackson, I. J., Korsmeyer, S. J., Golub, T. R., Fisher, D. E. <strong>Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.</strong> Cell 109: 707-718, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12086670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12086670</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00762-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12086670">McGill et al. (2002)</a>. Among identified targets was BCL2 (<a href="/entry/151430">151430</a>), whose germline deletion produced melanocyte loss and exhibited phenotypic synergy with Mitf in mice. The regulation of BCL2 by MITF was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. MITF was found to regulate BCL2 in osteoclasts, and both Mitf mi/mi and Bcl2 -/- mice exhibited severe osteopetrosis. Disruption of MITF in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helped explain the vital roles of both MITF and BCL2 in the melanocyte lineage and the well-known treatment resistance of melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12086670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Mitf-Tfe family of hHLH-leucine zipper (ZIP) translocation factors comprises 4 members: MITF, TFE3, TFEB (<a href="/entry/600744">600744</a>), and TFEC (<a href="/entry/604732">604732</a>). In vitro, each protein in the family can bind DNA as a homo- or heterodimer with other family members. Mutational studies in mice have shown that Mitf is essential for melanocyte and eye development consistent with the causation of a form of Waardenburg syndrome, whereas Tfeb is required for placenta vascularization. <a href="#31" class="mim-tip-reference" title="Steingrimsson, E., Tessarollo, L., Pathak, B., Hou, L., Arnheiter, H., Copeland, N. G., Jenkins, N. A. <strong>Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development.</strong> Proc. Nat. Acad. Sci. 99: 4477-4482, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930005[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.072071099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930005">Steingrimsson et al. (2002)</a> uncovered a role for Tfe3 in osteoclast development that is functionally redundant with that of Mitf. Although osteoclasts seem normal in Mitf or Tfe3 null mice, the combined loss of the 2 genes resulted in severe osteopetrosis. <a href="#31" class="mim-tip-reference" title="Steingrimsson, E., Tessarollo, L., Pathak, B., Hou, L., Arnheiter, H., Copeland, N. G., Jenkins, N. A. <strong>Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development.</strong> Proc. Nat. Acad. Sci. 99: 4477-4482, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930005[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.072071099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930005">Steingrimsson et al. (2002)</a> also showed that Tfec mutant mice were phenotypically normal, and that the Tfec mutation does not alter the phenotype of Mitf, Tfeb, or Tfe3 mutant mice. Their studies failed to identify any phenotypic overlap between the different Mitf-Tfe mutations. These results suggested that heterodimeric interactions are not essential for Mitf-Tfe function, in contrast to other bHLH-ZIP families like Myc/Max/Mad, where heterodimeric interactions seem to be essential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11930005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Selzer, E., Wacheck, V., Lucas, T., Heere-Ress, E., Wu, M., Weilbaecher, K. N., Schlegel, W., Valent, P., Wrba, F., Pehamberger, H., Fisher, D., Jansen, B. <strong>The melanocyte-specific isoform of the microphthalmia transcription factor affects the phenotype of human melanoma.</strong> Cancer Res. 62: 2098-2103, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11929831/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11929831</a>]" pmid="11929831">Selzer et al. (2002)</a> found that MITF-M was repressed in 8 of 14 established melanoma cell lines tested. Transfection of MITF-M into a melanoma cell line lacking the MITF-M isoform and into a permanent cell line established from normal melanocytes resulted in slower tumor growth. In addition to growth-inhibitory effects, MITF-M expression led to a change in the histopathologic appearance of tumors from epitheloid toward a spindle-cell type in vivo. These results indicated a role for the MITF-M isoform in the in vivo growth control and phenotype of melanoma. Thus, MITF-M may qualify as a marker capable of identifying subgroups of melanoma patients with different tumor biology and prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11929831" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Widlund, H. R., Horstmann, M. A., Price, E. R., Cui, J., Lessnick, S. L., Wu, M., He, X., Fisher, D. E. <strong>Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor.</strong> J. Cell Biol. 158: 1079-1087, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12235125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12235125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12235125[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/10.1083/jcb.200202049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12235125">Widlund et al. (2002)</a> identified beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) as a significant regulator of melanoma cell growth, with MITF as a critical downstream target. Disruption of the canonical Wnt (see <a href="/entry/164820">164820</a>) pathway abrogated growth of melanoma cells, and constitutive overexpression of MITF rescued the growth suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12235125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Yasumoto, K., Takeda, K., Saito, H., Watanabe, K., Takahashi, K., Shibahara, S. <strong>Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling.</strong> EMBO J. 21: 2703-2714, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12032083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12032083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12032083[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/21.11.2703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12032083">Yasumoto et al. (2002)</a> found that functional cooperation between MITF-M and LEF1 (<a href="/entry/153245">153245</a>) in several mammalian cell lines resulted in synergistic transactivation of the DCT promoter, an early melanoblast marker. Beta-catenin was required for efficient transactivation, but was dispensable for the interaction between MITF-M and LEF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12032083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Vetrini, F., Auricchio, A., Du, J., Angeletti, B., Fisher, D. E., Ballabio, A., Marigo, V. <strong>The microphthalmia transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: link between melanin synthesis and melanosome biogenesis.</strong> Molec. Cell. Biol. 24: 6550-6559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15254223[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.24.15.6550-6559.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15254223">Vetrini et al. (2004)</a> identified an E-box MITF-M-binding element within the OA1 (GPR143; <a href="/entry/300808">300808</a>) promoter. Using several in vitro and in vivo approaches, they confirmed that MTF-M bound the OA1 E-box and could drive expression of OA1 in human and mouse melanocytes and retinal pigment epithelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15254223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 addition to its role in melanocyte and melanoma survival and cell cycle progression, <a href="#7" class="mim-tip-reference" title="Carreira, S., Goodall, J., Aksan, I., La Rocca, S. A., Galibert, M.-D., Denat, L., Larue, L., Goding, C. R. <strong>Mitf cooperates with Rb1 and activates p21(Cip1) expression to regulate cell cycle progression.</strong> Nature 433: 764-769, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15716956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15716956</a>] [<a href="https://doi.org/10.1038/nature03269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15716956">Carreira et al. (2005)</a> showed that MITF can act as a novel antiproliferative transcription factor able to induce a G1 cell cycle arrest that is dependent on MITF-mediated activation of the p21(Cip1) (CDKN1A; <a href="/entry/116899">116899</a>) cyclin-dependent kinase inhibitor gene. Moreover, cooperation between MITF and RB1 (<a href="/entry/614041">614041</a>) potentiates the ability of MITF to activate transcription. <a href="#7" class="mim-tip-reference" title="Carreira, S., Goodall, J., Aksan, I., La Rocca, S. A., Galibert, M.-D., Denat, L., Larue, L., Goding, C. R. <strong>Mitf cooperates with Rb1 and activates p21(Cip1) expression to regulate cell cycle progression.</strong> Nature 433: 764-769, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15716956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15716956</a>] [<a href="https://doi.org/10.1038/nature03269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15716956">Carreira et al. (2005)</a> suggested that MITF-mediated activation of p21(Cip1) expression and consequent hypophosphorylation of RB1 contributes to cell cycle exit and activation of the differentiation program. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15716956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 human melanocytes and melanoma cell lines, <a href="#8" class="mim-tip-reference" title="Carreira, S., Goodall, J., Denat, L., Rodriguez, M., Nuciforo, P., Hoek, K. S., Testori, A., Larue, L., Goding, C. R. <strong>Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.</strong> Genes Dev. 20: 3426-3439, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17182868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17182868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17182868[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.406406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17182868">Carreira et al. (2006)</a> identified MITF as a regulator of DIA1 (DIAPH1; <a href="/entry/602121">602121</a>), a protein that controls actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Since DIA1 also regulates SKP2 (<a href="/entry/601436">601436</a>), an F-box protein that promotes degradation of p27(Kip1) (CDKN1B; <a href="/entry/600778">600778</a>), depletion of MITF led to downregulation of DIA1, followed by p27(Kip1)-dependent G1 arrest, reorganization of the actin cytoskeleton, and increased cellular invasiveness. In contrast, increased MITF expression promoted proliferation. <a href="#8" class="mim-tip-reference" title="Carreira, S., Goodall, J., Denat, L., Rodriguez, M., Nuciforo, P., Hoek, K. S., Testori, A., Larue, L., Goding, C. R. <strong>Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.</strong> Genes Dev. 20: 3426-3439, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17182868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17182868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17182868[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.406406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17182868">Carreira et al. (2006)</a> concluded that variations in environmental cues that determine MITF activity dictate the differentiation, proliferative, and invasive/migratory potential of melanoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17182868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, <a href="#10" class="mim-tip-reference" title="Garraway, L. A., Widlund, H. R., Rubin, M. A., Getz, G., Berger, A. J., Ramaswamy, S., Beroukhim, R., Milner, D. A., Granter, S. R., Du, J., Lee, C., Wagner, S. N., Li, C., Golub, T. R., Rimm, D. L., Meyerson, M. L., Fisher, D. E., Sellers, W. R. <strong>Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.</strong> Nature 436: 117-122, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16001072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16001072</a>] [<a href="https://doi.org/10.1038/nature03664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16001072">Garraway et al. (2005)</a> identified the melanocyte master regulator MITF as the target of a novel melanoma amplification. <a href="#10" class="mim-tip-reference" title="Garraway, L. A., Widlund, H. R., Rubin, M. A., Getz, G., Berger, A. J., Ramaswamy, S., Beroukhim, R., Milner, D. A., Granter, S. R., Du, J., Lee, C., Wagner, S. N., Li, C., Golub, T. R., Rimm, D. L., Meyerson, M. L., Fisher, D. E., Sellers, W. R. <strong>Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.</strong> Nature 436: 117-122, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16001072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16001072</a>] [<a href="https://doi.org/10.1038/nature03664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16001072">Garraway et al. (2005)</a> found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF (<a href="/entry/164757">164757</a>) mutation and p16 (CDKN2A; <a href="/entry/600160">600160</a>) inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF mutant (V600E; <a href="/entry/164757#0001">164757.0001</a>) transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. <a href="#10" class="mim-tip-reference" title="Garraway, L. A., Widlund, H. R., Rubin, M. A., Getz, G., Berger, A. J., Ramaswamy, S., Beroukhim, R., Milner, D. A., Granter, S. R., Du, J., Lee, C., Wagner, S. N., Li, C., Golub, T. R., Rimm, D. L., Meyerson, M. L., Fisher, D. E., Sellers, W. R. <strong>Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.</strong> Nature 436: 117-122, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16001072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16001072</a>] [<a href="https://doi.org/10.1038/nature03664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16001072">Garraway et al. (2005)</a> suggested that targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. <a href="#10" class="mim-tip-reference" title="Garraway, L. A., Widlund, H. R., Rubin, M. A., Getz, G., Berger, A. J., Ramaswamy, S., Beroukhim, R., Milner, D. A., Granter, S. R., Du, J., Lee, C., Wagner, S. N., Li, C., Golub, T. R., Rimm, D. L., Meyerson, M. L., Fisher, D. E., Sellers, W. R. <strong>Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.</strong> Nature 436: 117-122, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16001072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16001072</a>] [<a href="https://doi.org/10.1038/nature03664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16001072">Garraway et al. (2005)</a> concluded that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumor progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16001072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Larribere, L., Hilmi, C., Khaled, M., Gaggioli, C., Bille, K., Auberger, P., Ortonne, J. P., Ballotti, R., Bertolotto, C. <strong>The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis.</strong> Genes Dev. 19: 1980-1985, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16140982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16140982</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16140982[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.335905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16140982">Larribere et al. (2005)</a> found a role for MITF in apoptosis. They demonstrated that MITF is a caspase-3 (CASP3; <a href="/entry/600636">600636</a>) substrate and cleavage of MITF within its C-terminal domain releases a proapoptotic C-terminal fragment. Expression of a noncleavable form of MITF rendered melanoma cells resistant to apoptotic stimuli. Using small interfering RNA directed against MITF, <a href="#18" class="mim-tip-reference" title="Larribere, L., Hilmi, C., Khaled, M., Gaggioli, C., Bille, K., Auberger, P., Ortonne, J. P., Ballotti, R., Bertolotto, C. <strong>The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis.</strong> Genes Dev. 19: 1980-1985, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16140982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16140982</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16140982[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.335905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16140982">Larribere et al. (2005)</a> found that downregulation of MITF alone did not induce apoptosis, but expression of the C-terminal fragment sensitized melanoma cells to apoptotic stimuli. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16140982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Loercher, A. E., Tank, E. M. H., Delston, R. B., Harbour, J. W. <strong>MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A.</strong> J. Cell Biol. 168: 35-40, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15623583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15623583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15623583[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/10.1083/jcb.200410115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15623583">Loercher et al. (2005)</a> showed that expression of MITF in mouse embryonic fibroblasts resulted in marked growth inhibition and morphologic changes consistent with melanocyte differentiation. MITF regulated cell cycle exit by activating the cell cycle inhibitor INK4A (CDKN2A). MITF bound the INK4A promoter, activated p16(INK4A) mRNA and protein expression, and induced RB1 protein hypophosphorylation, thereby triggering cell cycle arrest. Activation of INK4A was required for efficient melanocyte differentiation, and MITF was required to maintain INK4A expression in mature melanocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15623583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 reporter gene assay, <a href="#4" class="mim-tip-reference" title="Bemis, L. T., Chen, R., Amato, C. M., Classen, E. H., Robinson, S. E., Coffey, D. G., Erickson, P. F., Shellman, Y. G., Robinson, W. A. <strong>MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines.</strong> Cancer Res. 68: 1362-1368, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18316599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18316599</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-07-2912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18316599">Bemis et al. (2008)</a> identified a functional microRNA-137 (MIR137; <a href="/entry/614304">614304</a>)-binding site in the 3-prime UTR of the MITF transcript. They also identified a variable nucleotide tandem repeat (VNTR) in the 5-prime region of the MIR137 gene that appeared to influence MIR137 expression. In cell lines with 12 VNTRs in this region, the primary MIR137 transcript had an altered secondary structure and was inefficiently processed to mature MIR137, leading to inefficient MITF downregulation. In contrast, cell lines with only 3 VNTRs upstream of MIR137 showed efficient downregulation of MITF expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18316599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Segura, M. F., Hanniford, D., Menendez, S., Reavie, L., Zou, X., Alvarez-Diaz, S., Zakrzewski, J., Blochin, E., Rose, A., Bogunovic, D., Polsky, D., Wei, J., Lee, P., Belitskaya-Levy, I., Bhardwaj, N., Osman, I., Hernando, E. <strong>Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor.</strong> Proc. Nat. Acad. Sci. 106: 1814-1819, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19188590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19188590</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19188590[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.0808263106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19188590">Segura et al. (2009)</a> identified FOXO3 (<a href="/entry/602681">602681</a>) and MITF as putative targets of MIR182 (<a href="/entry/611607">611607</a>) and showed that expression of MIR182 inversely correlated with FOXO3 and MITF levels in metastatic melanomas. MIR182 overexpression promoted migration and survival by direct repression of FOXO3 and MITF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19188590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. <a href="#25" class="mim-tip-reference" title="Perera, R. M., Stoykova, S., Nicolay, B. N., Ross, K. N., Fitamant, J., Boukhali, M., Lengrand, J., Deshpande, V., Selig, M. K., Ferrone, C. R., Settleman, J., Stephanopoulos, G., Dyson, N. J., Zoncu, R., Ramaswamy, S., Haas, W., Bardeesy, N. <strong>Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.</strong> Nature 524: 361-365, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26168401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26168401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26168401[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/nature14587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26168401">Perera et al. (2015)</a> showed that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins (MITF; TFE3, <a href="/entry/314310">314310</a>; and TFEB, <a href="/entry/600744">600744</a>) are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling revealed that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. <a href="#25" class="mim-tip-reference" title="Perera, R. M., Stoykova, S., Nicolay, B. N., Ross, K. N., Fitamant, J., Boukhali, M., Lengrand, J., Deshpande, V., Selig, M. K., Ferrone, C. R., Settleman, J., Stephanopoulos, G., Dyson, N. J., Zoncu, R., Ramaswamy, S., Haas, W., Bardeesy, N. <strong>Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.</strong> Nature 524: 361-365, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26168401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26168401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26168401[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/nature14587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26168401">Perera et al. (2015)</a> concluded that their results identified the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrated that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26168401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse and human mast cells and rat basophil leukemia (RBL) cells, <a href="#28" class="mim-tip-reference" title="Sharkia, I., Hadad Erlich, T., Landolina, N., Assayag, M., Motzik, A., Rachmin, I., Kay, G., Porat, Z., Tshori, S., Berkman, N., Levi-Schaffer, F., Razin, E. <strong>Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor.</strong> J. Allergy Clin. Immun. 140: 204-214, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27871875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27871875</a>] [<a href="https://doi.org/10.1016/j.jaci.2016.09.047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27871875">Sharkia et al. (2017)</a> showed that inhibition of pyruvate dehydrogenase (PDH; see <a href="/entry/300502">300502</a>) decreased degranulation and cytokine secretion. In mice, PDH inhibition decreased histamine secretion and lung resistance, but not airway inflammation. Yeast 2-hybrid, immunoprecipitation, and Western blot analyses showed that mouse Mitf interacted with the E1 subunit of PDH and that this interaction occurred after immunologic activation. Western blot, cell fractionation, and flow cytometric analyses demonstrated localization of Mitf to mitochondria. Overexpression of Mitf or Mitf lacking the leucine zipper domain resulted in decreased PDH activity, increased pyruvate activity, and reduced ATP and oxygen consumption levels in RBL cells. <a href="#28" class="mim-tip-reference" title="Sharkia, I., Hadad Erlich, T., Landolina, N., Assayag, M., Motzik, A., Rachmin, I., Kay, G., Porat, Z., Tshori, S., Berkman, N., Levi-Schaffer, F., Razin, E. <strong>Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor.</strong> J. Allergy Clin. Immun. 140: 204-214, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27871875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27871875</a>] [<a href="https://doi.org/10.1016/j.jaci.2016.09.047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27871875">Sharkia et al. (2017)</a> concluded that association of MITF with PDH is an important regulator of mast cell function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27871875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#36" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Read, A. P. <strong>Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.</strong> Nature Genet. 8: 251-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874167</a>] [<a href="https://doi.org/10.1038/ng1194-251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874167">Tassabehji et al. (1994)</a> demonstrated that the human MITF gene has 9 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Udono, T., Yasumoto, K., Takeda, K., Amae, S., Watanabe, K., Saito, H., Fuse, N., Tachibana, M., Takahashi, K., Tamai, M., Shibahara, S. <strong>Structural organization of the human microphthalmia-associated transcription factor gene containing four alternative promoters.</strong> Biochim. Biophys. Acta 1491: 205-219, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10760582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10760582</a>] [<a href="https://doi.org/10.1016/s0167-4781(00)00051-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10760582">Udono et al. (2000)</a> determined that the MITF gene contains 12 exons. The first 4 exons are differentially spliced to encode the unique N termini of the MITF isoforms. All MITF variants contain 8 common downstream exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10760582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 somatic cell hybrid studies and fluorescence in situ hybridization, <a href="#32" class="mim-tip-reference" title="Tachibana, M., Perez-Jurado, L. A., Nakayama, A., Hodgkinson, C. A., Li, X., Schneider, M., Miki, T., Fex, J., Francke, U., Arnheiter, H. <strong>Cloning of MITF, the human homolog of the mouse microphthalmia gene and assignment to chromosome 3p14.1-p12.3.</strong> Hum. Molec. Genet. 3: 553-557, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069297</a>] [<a href="https://doi.org/10.1093/hmg/3.4.553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069297">Tachibana et al. (1994)</a> mapped the human MITF gene to a region of chromosome 3 that shows a disrupted syntenic conservation with the region on mouse chromosome 6 to which mi maps, namely, 3p14.1-p12.3. As the human MITF gene was found to reside on chromosome 3, <a href="#32" class="mim-tip-reference" title="Tachibana, M., Perez-Jurado, L. A., Nakayama, A., Hodgkinson, C. A., Li, X., Schneider, M., Miki, T., Fex, J., Francke, U., Arnheiter, H. <strong>Cloning of MITF, the human homolog of the mouse microphthalmia gene and assignment to chromosome 3p14.1-p12.3.</strong> Hum. Molec. Genet. 3: 553-557, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069297</a>] [<a href="https://doi.org/10.1093/hmg/3.4.553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069297">Tachibana et al. (1994)</a> suggested that it may be involved in cases of Waardenburg syndrome type 2 that do not show linkage to the PAX3 (<a href="/entry/606597">606597</a>) locus on chromosome 2. The ermine phenotype, or BADS syndrome (<a href="/entry/227010">227010</a>), was also mentioned as a possible homolog. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#36" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Read, A. P. <strong>Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.</strong> Nature Genet. 8: 251-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874167</a>] [<a href="https://doi.org/10.1038/ng1194-251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874167">Tassabehji et al. (1994)</a> demonstrated mutations in the MITF gene in affected individuals in 2 families segregating Waardenburg syndrome type 2A (WS2A; <a href="/entry/193510">193510</a>). Both mutations affected splice sites in the MITF gene. One might expect that the MITF mutations would result in abnormal proteins which, when combined with the normal protein, would make dysfunctional dimers. Neither of the mutations appeared to function in that way, and <a href="#36" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Read, A. P. <strong>Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.</strong> Nature Genet. 8: 251-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874167</a>] [<a href="https://doi.org/10.1038/ng1194-251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874167">Tassabehji et al. (1994)</a> suggested possible explanations. They also pointed out that Waardenburg syndrome type II is relatively ill-defined, since hearing loss is not universal and the distinction in families with dominant white forelock or dominant heterochromia is often not clear. Furthermore, there are families in which unaffected but sometimes consanguineous parents have children with pigmentary disturbances sometimes combined with hearing loss and/or Hirschsprung disease. In the case of these apparently recessive syndromes, MITF was considered a good candidate for the mutant gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D., Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon, W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., Read, A. P. <strong>The mutational spectrum in Waardenburg syndrome.</strong> Hum. Molec. Genet. 4: 2131-2137, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589691</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589691">Tassabehji et al. (1995)</a> concluded that Waardenburg syndrome type II is heterogeneous, with about 20% of cases caused by mutations in MITF. In the mouse, mi mutations can be dominant or recessive. Dominant alleles are believed to work by a dominant-negative effect. A protein with intact helix-loop-helix and zipper sequences but defective DNA binding or transactivation domains sequesters the normal gene products in inactive dimers. Mutations that prevent dimerization are recessive. <a href="#35" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D., Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon, W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., Read, A. P. <strong>The mutational spectrum in Waardenburg syndrome.</strong> Hum. Molec. Genet. 4: 2131-2137, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589691</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589691">Tassabehji et al. (1995)</a> noted that most of the mouse mutations are recessive and most of the human mutations in MITF appear to be dominant. They concluded that MITF is another example of a gene like RET (<a href="/entry/164761">164761</a>) or PAX3 in which humans are more sensitive than mice to gene dosage effects in heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Tietz Albinism-Deafness Syndrome</em></strong></p><p>
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In a family with partial albinism and sensorineural deafness (Tietz albinism-deafness syndrome, TADS; <a href="/entry/103500">103500</a>), <a href="#35" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D., Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon, W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., Read, A. P. <strong>The mutational spectrum in Waardenburg syndrome.</strong> Hum. Molec. Genet. 4: 2131-2137, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589691</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589691">Tassabehji et al. (1995)</a> identified the exact equivalent of the mouse microphthalmia mutation, namely a deletion of 1 of a run of 4 arginines in the basic domain (R217del; <a href="#0003">156845.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 affected members of the family with hypopigmentation and deafness reported by <a href="#38" class="mim-tip-reference" title="Tietz, W. <strong>A syndrome of deaf-mutism associated with albinism showing dominant autosomal inheritance.</strong> Am. J. Hum. Genet. 15: 259-264, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13985019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13985019</a>]" pmid="13985019">Tietz (1963)</a>, <a href="#29" class="mim-tip-reference" title="Smith, S. D., Kelley, P. M., Kenyon, J. B., Hoover, D. <strong>Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF.</strong> J. Med. Genet. 37: 446-448, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10851256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10851256</a>] [<a href="https://doi.org/10.1136/jmg.37.6.446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10851256">Smith et al. (2000)</a> identified a mutation in the MITF gene (<a href="#0006">156845.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13985019+10851256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 24-year-old woman with Tietz syndrome, <a href="#13" class="mim-tip-reference" title="Izumi, K., Kohta, T., Kimura, Y., Ishida, S., Takahashi, T., Ishiko, A., Kosaki, K. <strong>Tietz syndrome: unique phenotype specific to mutations of MITF nuclear localization signal. (Letter)</strong> Clin. Genet. 74: 93-95, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18510545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18510545</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01010.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18510545">Izumi et al. (2008)</a> identified heterozygosity for the R217del mutation in the MITF gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18510545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness</em></strong></p><p>
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In 2 unrelated children with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; <a href="/entry/617306">617306</a>), whose parents exhibited features of WS2A, <a href="#11" class="mim-tip-reference" title="George, A., Zand, D. J., Hufnagel, R. B., Sharma, R., Sergeev, R., Sergeev, Y. V., Legare, J. M., Rice, G. M., Scott Schwoerer, J. A., Rius, M., Tetri, L., Gamm, D. M., Bharti, K., Brooks, B. P. <strong>Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness.</strong> Am. J. Hum. Genet. 99: 1388-1394, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889061">George et al. (2016)</a> identified compound heterozygosity for mutations in the MITF gene (<a href="#0003">156845.0003</a> and <a href="#0010">156845.0010</a>-<a href="#0012">156845.0012</a>). The parents in both families were each heterozygous for 1 of the mutations, as were the probands' sibs who showed features similar to those in the parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Cutaneous Malignant Melanoma 8, Susceptibility to</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Bertolotto, C., Lesueur, F., Giuliano, S., Strub, T., de Lichy, M., Bille, K., Dessen, P., d'Hayer, B., Mohamdi, H., Remenieras, A., Maubec, E., de la Fouchardiere, A., and 45 others. <strong>A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.</strong> Nature 480: 94-98, 2011. Note: Erratum: Nature 531: 126 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22012259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22012259</a>] [<a href="https://doi.org/10.1038/nature10539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22012259">Bertolotto et al. (2011)</a> identified a missense mutation in MITF (E318K; <a href="#0009">156845.0009</a>) that greatly increases the risk of malignant melanoma and/or renal cell carcinoma in carriers, with an odds ratio of 14.46 (95% CI 3.74-48.04) for the risk of melanoma plus renal cell carcinoma. <a href="#45" class="mim-tip-reference" title="Yokoyama, S., Woods, S. L., Boyle, G. M., Aoude, L. G., MacGregor, S., Zismann, V., Gartside, M., Cust, A. E., Haq, R., Harland, M., Taylor, J. C., Duffy, D. L., and 35 others. <strong>A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.</strong> Nature 480: 99-103, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22080950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22080950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22080950[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/nature10630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22080950">Yokoyama et al. (2011)</a> independently identified the E318K mutation in the MITF gene as increasing the risk of melanoma in both families and sporadic cases. The variant cosegregated with melanoma in some, but not all, cases of melanoma in the initial family identified, but linkage analysis of 31 families subsequently identified to carry the variant generated a lod score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case control sample. Likewise, it was similarly associated in an independent case control sample from the United Kingdom. <a href="#45" class="mim-tip-reference" title="Yokoyama, S., Woods, S. L., Boyle, G. M., Aoude, L. G., MacGregor, S., Zismann, V., Gartside, M., Cust, A. E., Haq, R., Harland, M., Taylor, J. C., Duffy, D. L., and 35 others. <strong>A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.</strong> Nature 480: 99-103, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22080950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22080950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22080950[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/nature10630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22080950">Yokoyama et al. (2011)</a> also showed that E318K prevents MITF sumoylation and results in differential expression of MITF target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22080950+22012259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#30" class="mim-tip-reference" title="Steingrimsson, E., Moore, K. J., Lamoreux, M. L., Ferre-D'Amare, A. R., Burley, S. K., Sanders Zimring, D. C., Skow, L. C., Hodgkinson, C. A., Arnheiter, H., Copeland, N. G., Jenkins, N. A. <strong>Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences.</strong> Nature Genet. 8: 256-263, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874168</a>] [<a href="https://doi.org/10.1038/ng1194-256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874168">Steingrimsson et al. (1994)</a> characterized the molecular defects associated with 8 murine mi mutations, which vary both in their mode of inheritance and in the cell types they affect. These molecular data provided insight into the phenotypic and developmental consequences of mi mutations and offered a mouse model for WS2. <a href="#14" class="mim-tip-reference" title="Jackson, I. J., Raymond, S. <strong>Manifestations of microphthalmia.</strong> Nature Genet. 8: 209-210, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874158</a>] [<a href="https://doi.org/10.1038/ng1194-209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874158">Jackson and Raymond (1994)</a> and <a href="#21" class="mim-tip-reference" title="Moore, K. J. <strong>Insight into the microphthalmia gene.</strong> Trends Genet. 11: 442-448, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8578601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8578601</a>] [<a href="https://doi.org/10.1016/s0168-9525(00)89143-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8578601">Moore (1995)</a> provided commentaries. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7874158+8578601+7874168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 anophthalmic white (Wh) mutation in Syrian hamsters causes pigmentation abnormalities and variable hearing loss in heterozygotes and absence of pigmentation, profound deafness, and severe eye reduction in homozygotes. <a href="#12" class="mim-tip-reference" title="Hodgkinson, C. A., Nakayama, A., Li, H., Swenson, L.-B., Opdecamp, K., Asher, J. H., Jr., Arnheiter, H., Glaser, T. <strong>Mutation at the anophthalmic white locus in Syrian hamsters: haploinsufficiency in the Mitf gene mimics human Waardenburg syndrome type 2.</strong> Hum. Molec. Genet. 7: 703-708, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499424</a>] [<a href="https://doi.org/10.1093/hmg/7.4.703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499424">Hodgkinson et al. (1998)</a> determined that the Wh phenotype is caused by a nonsense mutation in the hamster Mitf gene that truncates the protein between helices 1 and 2 of the DNA-binding and dimerization domain. The mRNA is destabilized, and the protein is unable to dimerize or bind DNA target sites. The mutant protein does not act through a dominant-negative mechanism, and the Wh mutation is inherited as a semidominant trait. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9499424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Thaung, C., West, K., Clark, B. J., McKie, L., Morgan, J. E., Arnold, K., Nolan, P. M., Peters, J., Hunter, A. J., Brown, S. D. M., Jackson, I. J., Cross, S. H. <strong>Novel ENU-induced eye mutations in the mouse: models for human eye disease.</strong> Hum. Molec. Genet. 11: 755-767, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11929848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11929848</a>] [<a href="https://doi.org/10.1093/hmg/11.7.755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11929848">Thaung et al. (2002)</a> carried out a genomewide screen for novel N-ethyl-N-nitrosourea-induced mutations that give rise to eye and vision abnormalities in the mouse, and identified 25 inherited phenotypes that affect all parts of the eye. A combination of genetic mapping, complementation, and molecular analysis revealed that 14 of these were mutations in genes previously identified to play a role in eye pathophysiology, namely Pax6 (<a href="/entry/607108">607108</a>), Mitf, Egfr (<a href="/entry/131550">131550</a>), and Pde6b (<a href="/entry/180072">180072</a>). Many of the others were located in genomic regions lacking candidate genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11929848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 PCR, Western blot, and immunohistochemical analyses, <a href="#39" class="mim-tip-reference" title="Tshori, S., Gilon, D., Beeri, R., Nechushtan, H., Kaluzhny, D., Pikarsky, E., Razin, E. <strong>Transcription factor MITF regulates cardiac growth and hypertrophy.</strong> J. Clin. Invest. 116: 2673-2681, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16998588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16998588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16998588[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/10.1172/JCI27643" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16998588">Tshori et al. (2006)</a> found that Mitf was expressed in cardiomyocytes from wildtype mice, but not in tg/tg mice, which have a 50-copy insertion of a transgene in the Mitf promoter region. The ratio of heart weight to body weight was reduced in tg/tg mice and ce/ ce mice, which lack the Zip domain of the Mitf protein. In response to beta-adrenergic stimulation, the Mitf mutant mouse strains had reduced hypertrophic responses and did not produce increased levels of Bnp (NPPB; <a href="/entry/600295">600295</a>). <a href="#39" class="mim-tip-reference" title="Tshori, S., Gilon, D., Beeri, R., Nechushtan, H., Kaluzhny, D., Pikarsky, E., Razin, E. <strong>Transcription factor MITF regulates cardiac growth and hypertrophy.</strong> J. Clin. Invest. 116: 2673-2681, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16998588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16998588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16998588[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/10.1172/JCI27643" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16998588">Tshori et al. (2006)</a> concluded that MITF plays an essential role in beta-adrenergic-induced cardiac hypertrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16998588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="George, A., Zand, D. J., Hufnagel, R. B., Sharma, R., Sergeev, R., Sergeev, Y. V., Legare, J. M., Rice, G. M., Scott Schwoerer, J. A., Rius, M., Tetri, L., Gamm, D. M., Bharti, K., Brooks, B. P. <strong>Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness.</strong> Am. J. Hum. Genet. 99: 1388-1394, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889061">George et al. (2016)</a> expressed 2 human MITF mutations, R318del (<a href="#0003">156845.0003</a>) and K307N (<a href="#0010">156845.0010</a>), in 1-cell-stage zebrafish embryos and quantified melanocytes in the dorsal-trunk region at 34 to 36 hours postfertilization. Both mutations resulted in significantly lower numbers of melanocytes compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1553701477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553701477;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=rs1553701477" 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=rs1553701477" 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 family with type II Waardenburg syndrome (WS2A; <a href="/entry/193510">193510</a>) that showed linkage to markers on 3p in the vicinity of the MITF gene, <a href="#36" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Read, A. P. <strong>Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.</strong> Nature Genet. 8: 251-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874167</a>] [<a href="https://doi.org/10.1038/ng1194-251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874167">Tassabehji et al. (1994)</a> found that amplified DNA of exon 1 showed an abnormal band on SSCP/heteroduplex analysis. Sequencing demonstrated a GT-to-AT change, which would abolish the donor splice site at the end of exon 1. Two individuals were clinically ambiguous because one had hearing loss, which might have been attributable to a head injury, and the second had minor heterochromia as his only feature of Waardenburg syndrome. By linkage analysis and direct mutation testing, however, both of these individuals carried the MITF mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1553703612 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553703612;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=rs1553703612" 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=rs1553703612" 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 family with type 2A Waardenburg syndrome (WS2A; <a href="/entry/193510">193510</a>) showing linkage to markers on 3p in the vicinity of the MITF locus, <a href="#36" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Read, A. P. <strong>Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.</strong> Nature Genet. 8: 251-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874167</a>] [<a href="https://doi.org/10.1038/ng1194-251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874167">Tassabehji et al. (1994)</a> found that all affected members showed an abnormal SSCP band in amplified exon 5. Sequencing demonstrated that the AG acceptor splice site at the end of intron 4 had been mutated to CG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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COLOBOMA, OSTEOPETROSIS, MICROPHTHALMIA, MACROCEPHALY, ALBINISM, AND DEAFNESS, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553704814 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553704814;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=rs1553704814" 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=rs1553704814" 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=RCV000015342 OR RCV000498643 OR RCV000826199 OR RCV001290155 OR RCV001785452 OR RCV005222684" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015342, RCV000498643, RCV000826199, RCV001290155, RCV001785452, RCV005222684" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015342...</a>
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<p>In a family with partial albinism and sensorineural deafness (TADS; <a href="/entry/103500">103500</a>), <a href="#35" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D., Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon, W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., Read, A. P. <strong>The mutational spectrum in Waardenburg syndrome.</strong> Hum. Molec. Genet. 4: 2131-2137, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589691</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589691">Tassabehji et al. (1995)</a> identified the exact equivalent of the mouse microphthalmia mutation, namely a deletion of 1 of a run of 4 arginines in the basic domain. Following the mouse precedent, they labeled this mutation R217del, although from the DNA and protein sequences one could not say which of the 4 arginines was deleted. <a href="#2" class="mim-tip-reference" title="Amiel, J., Watkin, P. M., Tassabehji, M., Read, A. P., Winter, R. M. <strong>Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome).</strong> Clin. Dysmorph. 7: 17-20, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9546825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9546825</a>]" pmid="9546825">Amiel et al. (1998)</a> noted that although the affected mother and son fulfilled diagnostic criteria for Waardenburg syndrome type 2 (see <a href="/entry/193510">193510</a>), they more closely resembled the family reported by <a href="#38" class="mim-tip-reference" title="Tietz, W. <strong>A syndrome of deaf-mutism associated with albinism showing dominant autosomal inheritance.</strong> Am. J. Hum. Genet. 15: 259-264, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13985019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13985019</a>]" pmid="13985019">Tietz (1963)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8589691+13985019+9546825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 24-year-old woman with Tietz syndrome, <a href="#13" class="mim-tip-reference" title="Izumi, K., Kohta, T., Kimura, Y., Ishida, S., Takahashi, T., Ishiko, A., Kosaki, K. <strong>Tietz syndrome: unique phenotype specific to mutations of MITF nuclear localization signal. (Letter)</strong> Clin. Genet. 74: 93-95, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18510545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18510545</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01010.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18510545">Izumi et al. (2008)</a> identified heterozygosity for the R217del mutation in the MITF gene. The authors noted that dimerization between mutant and wildtype protein would reduce the number of intact wildtype dimers with access to the nucleus to 25% of normal. Histologic examination of skin biopsy specimens revealed the presence of melanocytes, suggesting that the migration of melanocyte stem cells from the neural crest to the epidermal layer occurred normally. In the hypopigmented regions, however, a reduction in the number of melanosomes in keratinocytes adjacent to the melanocytes suggested a disruption in the transfer of melanosomes from the melanocytes to the keratinocytes; and in the hyperpigmented regions, an increase in the number of melanosomes in the keratinocytes adjacent to HMB45-positive melanocytes pointed to a high level of melanogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18510545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 5-year-old boy with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; <a href="/entry/617306">617306</a>), <a href="#11" class="mim-tip-reference" title="George, A., Zand, D. J., Hufnagel, R. B., Sharma, R., Sergeev, R., Sergeev, Y. V., Legare, J. M., Rice, G. M., Scott Schwoerer, J. A., Rius, M., Tetri, L., Gamm, D. M., Bharti, K., Brooks, B. P. <strong>Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness.</strong> Am. J. Hum. Genet. 99: 1388-1394, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889061">George et al. (2016)</a> identified compound heterozygosity for mutations in the MITF gene: the first was a 3-bp deletion (c.952_954delAGA), which they stated corresponded to Arg318del in the MITF-A isoform and to Arg217del in the MITF-M isoform; the second was a c.921G-C transversion, resulting in a lys307-to-asn (K307N; <a href="#0010">156845.0010</a>) substitution in isoform MITF-A. The proband's parents and 1 brother, who exhibited features of WS2A, were each heterozygous for 1 of the mutations. The K307N mutation was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. Functional analysis showed that, unlike wildtype MITF, the R318del mutant did not migrate to the nucleus in transfected HEK293 cells or bind consensus M-box or E-box DNA sequences in vitro; in addition, this allele did not activate the tyrosinase (TYR; <a href="/entry/606933">606933</a>) promoter or repress the FGF19 (<a href="/entry/603891">603891</a>) promoter in dual luciferase reporter assays. In comparison, the K307N allele was distributed equally between the nucleus and the cytoplasm and exhibited approximately 20% of the DNA-binding capability of wildtype MITF, but had significant transcriptional regulatory potential on TYR and FGF19 promoters. Coexpression of R318del and K307N in HEK293 cells resulted in migration of only 30% of MITF into the nucleus, whereas coexpression of mutant with wildtype protein resulted in 36% or 81% migration, respectively. DNA binding of co-in-vitro-translated R318del and K307N was less than 20% of that of wildtype MITF for consensus E-box and M-box elements; wildtype with R318del resulted in approximately 50% reduction of DNA binding, whereas wildtype with K307N bound both consensus elements better than wildtype. Transcriptional activation of the TYRP1 (<a href="/entry/115501">115501</a>) promoter was reduced more dramatically when increasing amounts of R318del were coexpressed with K307N than with wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104893744 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893744;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=rs104893744" 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=rs104893744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In their family WS.115 with Waardenburg syndrome (WS2A; <a href="/entry/193510">193510</a>), <a href="#35" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D., Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon, W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., Read, A. P. <strong>The mutational spectrum in Waardenburg syndrome.</strong> Hum. Molec. Genet. 4: 2131-2137, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589691</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589691">Tassabehji et al. (1995)</a> identified a T-to-C mutation which changed codon 250 from TCC (ser) to CCC (pro). The patient was a woman with unilateral hearing loss and premature graying who had a son with unilateral hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1553705282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553705282;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=rs1553705282" 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=rs1553705282" 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=RCV000015344" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015344" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015344</a>
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<p><a href="#22" class="mim-tip-reference" title="Morell, R., Spritz, R. A., Ho, L., Pierpont, J., Guo, W., Friedman, T. B., Asher, J. H., Jr. <strong>Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA).</strong> Hum. Molec. Genet. 6: 659-664, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158138</a>] [<a href="https://doi.org/10.1093/hmg/6.5.659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9158138">Morell et al. (1997)</a> described apparent digenic inheritance of the combination of Waardenburg syndrome type II (WS2A; <a href="/entry/193510">193510</a>) and ocular albinism. In a family originally reported by <a href="#3" class="mim-tip-reference" title="Bard, L. A. <strong>Heterogeneity in Waardenburg's syndrome: report of a family with ocular albinism.</strong> Arch. Ophthal. 96: 1193-1198, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/666627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">666627</a>] [<a href="https://doi.org/10.1001/archopht.1978.03910060027006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="666627">Bard (1978)</a>, <a href="#22" class="mim-tip-reference" title="Morell, R., Spritz, R. A., Ho, L., Pierpont, J., Guo, W., Friedman, T. B., Asher, J. H., Jr. <strong>Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA).</strong> Hum. Molec. Genet. 6: 659-664, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158138</a>] [<a href="https://doi.org/10.1093/hmg/6.5.659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9158138">Morell et al. (1997)</a> found that affected individuals were heterozygous for a 1-bp deletion in codon 275 in exon 8 of the MITF gene, resulting in a frameshift and a TGA termination codon in exon 9. The affected individuals were also either homozygous or heterozygous for the arg402-to-gln polymorphism (R402Q) of the tyrosinase gene (TYR; <a href="/entry/606933#0009">606933.0009</a>). TYR gene expression is controlled by the MITF transcription factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=666627+9158138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 TIETZ ALBINISM-DEAFNESS SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893745 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893745;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=rs104893745" 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=rs104893745" 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=RCV000015345" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015345" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015345</a>
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<p><a href="#29" class="mim-tip-reference" title="Smith, S. D., Kelley, P. M., Kenyon, J. B., Hoover, D. <strong>Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF.</strong> J. Med. Genet. 37: 446-448, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10851256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10851256</a>] [<a href="https://doi.org/10.1136/jmg.37.6.446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10851256">Smith et al. (2000)</a> restudied the family with hypopigmentation and deafness (TADS; <a href="/entry/103500">103500</a>) reported by <a href="#38" class="mim-tip-reference" title="Tietz, W. <strong>A syndrome of deaf-mutism associated with albinism showing dominant autosomal inheritance.</strong> Am. J. Hum. Genet. 15: 259-264, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13985019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13985019</a>]" pmid="13985019">Tietz (1963)</a> and confirmed the existence of the syndrome through at least 4 generations. All affected individuals were born 'snow white,' but gradually gained some pigmentation, with fair skin and blond hair. Eyebrows and eyelashes remained blond. Hearing loss was always bilateral, congenital, and profound, and communication was primarily through signing. There was no variation in expression and penetrance was complete. Linkage to the region of MITF was demonstrated in the family and a unique heteroduplex pattern of exons 5 and 6 of MITF was found to segregate with affected members of the kindred. The change bordering exon 5 was adjacent to the splice junction consensus sequence. The change in exon 6 resulted in an asn210-to-lys amino acid substitution in the basic region of the transcription factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13985019+10851256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104893746 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893746;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=rs104893746" 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=rs104893746" 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=RCV000015346 OR RCV000414854 OR RCV000415265 OR RCV001200166 OR RCV001813988" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015346, RCV000414854, RCV000415265, RCV001200166, RCV001813988" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015346...</a>
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<p><a href="#16" class="mim-tip-reference" title="Lalwani, A. K., Attaie, A., Randolph, F. T., Deshmukh, D., Wang, C., Mhatre, A., Wilcox, E. <strong>Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family.</strong> Am. J. Med. Genet. 80: 406-409, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9856573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9856573</a>]" pmid="9856573">Lalwani et al. (1998)</a> reported a 3-generation Indian family with a point mutation in the MITF gene causing Waardenburg syndrome type 2A (WS2A; <a href="/entry/193510">193510</a>). Mutation screening of the MITF gene showed a 760C-T transition resulting in an arg214-to-ter nonsense mutation, predicted to result in a truncated MITF protein. The mutation occurred in a CpG dinucleotide. The R214X mutation was reported earlier in a northern European family by <a href="#24" class="mim-tip-reference" title="Nobukuni, Y., Watanabe, A., Takeda, K., Skarka, H., Tachibana, M. <strong>Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A.</strong> Am. J. Hum. Genet. 59: 76-83, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8659547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8659547</a>]" pmid="8659547">Nobukuni et al. (1996)</a>. Comparison of the phenotype of the 2 families demonstrated a significant difference in pigmentary disturbance of the eye. In both families, hearing loss was the most common finding, followed by ocular pigmentary disturbance. Heterochromia iridis occurred in 8 of 11 affected members of the Indian family and in 4 of 14 affected members of the European family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9856573+8659547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0008 WAARDENBURG SYNDROME, TYPE 2A</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"><span class="text-primary">●</span> rs104893747 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893747;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/rs104893747?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=rs104893747" 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=rs104893747" 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=RCV000015347 OR RCV001541066 OR RCV002281708 OR RCV002513060 OR RCV003974827 OR RCV004786263" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015347, RCV001541066, RCV002281708, RCV002513060, RCV003974827, RCV004786263" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015347...</a>
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<p><a href="#35" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Liu, X.-Z., Brady, A., Donnai, D., Krajewska-Walasek, M., Murday, V., Norman, A., Obersztyn, E., Reardon, W., Rice, J. C., Trembath, R., Wieacker, P., Whiteford, M., Winter, R., Read, A. P. <strong>The mutational spectrum in Waardenburg syndrome.</strong> Hum. Molec. Genet. 4: 2131-2137, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589691</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589691">Tassabehji et al. (1995)</a> found that affected members of a family with type 2 Waardenburg syndrome (WS2A; <a href="/entry/193510">193510</a>) had a ser298-to-pro substitution in their MITF gene. <a href="#34" class="mim-tip-reference" title="Takeda, K., Takemoto, C., Kobayashi, I., Watanabe, A., Nobukuni, Y., Fisher, D. E., Tachibana, M. <strong>Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance.</strong> Hum. Molec. Genet. 9: 125-132, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587587</a>] [<a href="https://doi.org/10.1093/hmg/9.1.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587587">Takeda et al. (2000)</a> showed that ser298, which is located downstream of the basic helix-loop-helix leucine zipper, plays an important role in MITF function. They found that glycogen synthase kinase-3 (GSK3) phosphorylated ser298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter. The same serine was found to be phosphorylated in vivo, and expression of dominant-negative GSK3-beta selectively suppressed the ability of MITF to transactivate the tyrosinase promoter. Moreover, mutation of ser298 disabled phosphorylation of MITF by GSK3-beta and impaired MITF function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8589691+10587587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs149617956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs149617956;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/rs149617956?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=rs149617956" 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=rs149617956" 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=RCV000022661 OR RCV000129682 OR RCV000222278 OR RCV000484916 OR RCV000627790 OR RCV001195106 OR RCV001535706 OR RCV002247378 OR RCV002490402" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022661, RCV000129682, RCV000222278, RCV000484916, RCV000627790, RCV001195106, RCV001535706, RCV002247378, RCV002490402" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022661...</a>
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<p><a href="#5" class="mim-tip-reference" title="Bertolotto, C., Lesueur, F., Giuliano, S., Strub, T., de Lichy, M., Bille, K., Dessen, P., d'Hayer, B., Mohamdi, H., Remenieras, A., Maubec, E., de la Fouchardiere, A., and 45 others. <strong>A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.</strong> Nature 480: 94-98, 2011. Note: Erratum: Nature 531: 126 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22012259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22012259</a>] [<a href="https://doi.org/10.1038/nature10539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22012259">Bertolotto et al. (2011)</a> identified a c.952G-A transition (c.952G-A, NM_000248.3) in the MITF gene (isoform MITF-M), resulting in a glu-to-lys substitution at codon 318 (E318K). This missense mutation was found at increased frequency in the germline of individuals with melanoma or renal cell carcinoma and at much increased frequency in individuals with both melanoma and renal cell carcinoma compared with controls. The overall allele frequency in controls was 0.003, in patients with melanoma and/or renal cell carcinoma it was 0.016, and among individuals with both melanoma and renal cell carcinoma it was 0.040. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22012259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Yokoyama, S., Woods, S. L., Boyle, G. M., Aoude, L. G., MacGregor, S., Zismann, V., Gartside, M., Cust, A. E., Haq, R., Harland, M., Taylor, J. C., Duffy, D. L., and 35 others. <strong>A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.</strong> Nature 480: 99-103, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22080950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22080950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22080950[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/nature10630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22080950">Yokoyama et al. (2011)</a> independently identified the E318K mutation in the MITF gene (isoform MITF-M) as increasing the risk of melanoma in both families and sporadic cases. The variant cosegregated with melanoma in some, but not all, cases of melanoma in the initial family identified, but linkage analysis of 31 families subsequently identified to carry the variant generated a lod score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. <a href="#45" class="mim-tip-reference" title="Yokoyama, S., Woods, S. L., Boyle, G. M., Aoude, L. G., MacGregor, S., Zismann, V., Gartside, M., Cust, A. E., Haq, R., Harland, M., Taylor, J. C., Duffy, D. L., and 35 others. <strong>A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.</strong> Nature 480: 99-103, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22080950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22080950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22080950[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/nature10630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22080950">Yokoyama et al. (2011)</a> also showed that E318K prevents MITF sumoylation and results in differential expression of MITF target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22080950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 COLOBOMA, OSTEOPETROSIS, MICROPHTHALMIA, MACROCEPHALY, ALBINISM, AND DEAFNESS</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">rs1057519325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519325;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=rs1057519325" 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=rs1057519325" 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=RCV000416286 OR RCV000416300" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416286, RCV000416300" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416286...</a>
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<p>For discussion of the c.921G-C transversion (c.921G-C, NM_198159.2) in the MITF gene (isoform MITF-A), resulting in a lys307-to-asn (K307N) substitution, that was found in compound heterozygous state in a 5-year-old boy with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; <a href="/entry/617306">617306</a>) by <a href="#11" class="mim-tip-reference" title="George, A., Zand, D. J., Hufnagel, R. B., Sharma, R., Sergeev, R., Sergeev, Y. V., Legare, J. M., Rice, G. M., Scott Schwoerer, J. A., Rius, M., Tetri, L., Gamm, D. M., Bharti, K., Brooks, B. P. <strong>Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness.</strong> Am. J. Hum. Genet. 99: 1388-1394, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889061">George et al. (2016)</a>, see <a href="#0003">156845.0003</a>. The proband's mother, who exhibited features of Waardenburg syndrome type 2A (WS2A; <a href="/entry/193510">193510</a>), was heterozygous for the K307N mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1057519326 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519326;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=rs1057519326" 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=rs1057519326" 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=RCV000416288 OR RCV000416308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416288, RCV000416308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416288...</a>
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<p>In a 9-month-old girl with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; <a href="/entry/617306">617306</a>), <a href="#11" class="mim-tip-reference" title="George, A., Zand, D. J., Hufnagel, R. B., Sharma, R., Sergeev, R., Sergeev, Y. V., Legare, J. M., Rice, G. M., Scott Schwoerer, J. A., Rius, M., Tetri, L., Gamm, D. M., Bharti, K., Brooks, B. P. <strong>Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness.</strong> Am. J. Hum. Genet. 99: 1388-1394, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889061">George et al. (2016)</a> identified compound heterozygosity for mutations in the MITF gene (MITF-A isoform): the first was a c.952A-G transition (c.952A-G, NM_198159.2), resulting in an arg318-to-gly (R318G) substitution; the second was a splice site mutation (c.938-1G-A), predicted to result in a premature termination codon (Leu312fsTer11; <a href="#0012">156845.0012</a>). The proband's parents and 3 sibs, who exhibited features of Waardenburg syndrome type 2A (WS2A; <a href="/entry/193510">193510</a>), were each heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1057519327 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519327;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=rs1057519327" 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=rs1057519327" 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=RCV000416298 OR RCV000416310 OR RCV003766173" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416298, RCV000416310, RCV003766173" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416298...</a>
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<p>For discussion of the c.938-1G-A transition (c.938-1G-A, NM_198159.2) in the MITF gene (MITF-A isoform), predicted to result in a premature termination codon (Leu312fsTer11), that was found in compound heterozygous state in a 9-month-old girl with COMMAD (<a href="/entry/617306">617306</a>) by <a href="#11" class="mim-tip-reference" title="George, A., Zand, D. J., Hufnagel, R. B., Sharma, R., Sergeev, R., Sergeev, Y. V., Legare, J. M., Rice, G. M., Scott Schwoerer, J. A., Rius, M., Tetri, L., Gamm, D. M., Bharti, K., Brooks, B. P. <strong>Biallelic mutations in MITF cause coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness.</strong> Am. J. Hum. Genet. 99: 1388-1394, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889061</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27889061[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889061">George et al. (2016)</a>, see <a href="#0011">156845.0011</a>. The proband's mother, who exhibited features of Waardenburg syndrome type 2A (WS2A; <a href="/entry/193510">193510</a>), was heterozygous for the splice site mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Aberdam, E., Bertolotto, C., Sviderskaya, E. V., de Thillot, V., Hemesath, T. J., Fisher, D. E., Bennett, D. C., Ortonne, J.-P., Ballotti, R.
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<strong>Involvement of microphthalmia in the inhibition of melanocyte lineage differentiation and of melanogenesis by agouti signal protein.</strong>
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J. Biol. Chem. 273: 19560-19565, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9677380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9677380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9677380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.31.19560" target="_blank">Full Text</a>]
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Amiel, J., Watkin, P. M., Tassabehji, M., Read, A. P., Winter, R. M.
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<strong>Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome).</strong>
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Clin. Dysmorph. 7: 17-20, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9546825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9546825</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9546825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587587</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/9.1.125" target="_blank">Full Text</a>]
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<a id="Tassabehji1995" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1093/hmg/4.11.2131" target="_blank">Full Text</a>]
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<strong>Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.</strong>
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[<a href="https://doi.org/10.1038/ng1194-251" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.7.755" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI27643" target="_blank">Full Text</a>]
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Udono, T., Yasumoto, K., Takeda, K., Amae, S., Watanabe, K., Saito, H., Fuse, N., Tachibana, M., Takahashi, K., Tamai, M., Shibahara, S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10760582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10760582</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10760582" 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/s0167-4781(00)00051-8" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15254223[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=15254223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.24.15.6550-6559.2004" target="_blank">Full Text</a>]
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<strong>Epistatic relationship between Waardenburg syndrome genes MITF and PAX3.</strong>
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[<a href="https://doi.org/10.1038/ng0398-283" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12235125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12235125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12235125[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=12235125" 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/10.1083/jcb.200202049" target="_blank">Full Text</a>]
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Yasumoto, K., Takeda, K., Saito, H., Watanabe, K., Takahashi, K., Shibahara, S.
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<strong>Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12032083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12032083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12032083[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=12032083" 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/emboj/21.11.2703" target="_blank">Full Text</a>]
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Yokoyama, S., Woods, S. L., Boyle, G. M., Aoude, L. G., MacGregor, S., Zismann, V., Gartside, M., Cust, A. E., Haq, R., Harland, M., Taylor, J. C., Duffy, D. L., and 35 others.
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<strong>A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.</strong>
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Nature 480: 99-103, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22080950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22080950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22080950[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=22080950" 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/nature10630" target="_blank">Full Text</a>]
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Paul J. Converse - updated : 08/15/2017
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Marla J. F. O'Neill - updated : 01/23/2017<br>Ada Hamosh - updated : 09/11/2015<br>Ada Hamosh - updated : 1/4/2012<br>Patricia A. Hartz - updated : 11/8/2011<br>Patricia A. Hartz - updated : 1/20/2010<br>Marla J. F. O'Neill - updated : 5/7/2009<br>Patricia A. Hartz - updated : 3/2/2007<br>Paul J. Converse - updated : 1/5/2007<br>Marla J. F. O'Neill - updated : 10/13/2006<br>Patricia A. Hartz - updated : 11/11/2005<br>Patricia A. Hartz - updated : 9/8/2005<br>Ada Hamosh - updated : 8/3/2005<br>Ada Hamosh - updated : 4/15/2005<br>George E. Tiller - updated : 2/21/2005<br>Victor A. McKusick - updated : 5/16/2003<br>George E. Tiller - updated : 10/25/2002<br>Victor A. McKusick - updated : 10/11/2002<br>Stylianos E. Antonarakis - updated : 8/6/2002<br>Michael J. Wright - updated : 10/5/2001<br>Victor A. McKusick - updated : 6/1/2001<br>George E. Tiller - updated : 10/20/2000<br>Ada Hamosh - updated : 8/1/2000<br>Victor A. McKusick - updated : 2/16/2000<br>Ada Hamosh - updated : 2/1/2000<br>Victor A. McKusick - updated : 12/30/1998<br>Victor A. McKusick - updated : 2/27/1998<br>Victor A. McKusick - updated : 10/22/1997<br>Victor A. McKusick - updated : 6/23/1997
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Victor A. McKusick : 6/21/1994
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alopez : 03/09/2022<br>alopez : 02/03/2020<br>alopez : 02/03/2020<br>mgross : 08/15/2017<br>carol : 01/24/2017<br>carol : 01/23/2017<br>carol : 11/29/2016<br>alopez : 08/01/2016<br>alopez : 09/11/2015<br>alopez : 1/30/2012<br>terry : 1/4/2012<br>mgross : 11/8/2011<br>terry : 11/8/2011<br>carol : 6/17/2011<br>ckniffin : 3/17/2010<br>carol : 3/11/2010<br>mgross : 1/20/2010<br>terry : 1/20/2010<br>mgross : 11/9/2009<br>wwang : 5/13/2009<br>terry : 5/7/2009<br>mgross : 3/2/2007<br>mgross : 1/5/2007<br>mgross : 1/5/2007<br>carol : 10/13/2006<br>terry : 10/13/2006<br>mgross : 12/5/2005<br>mgross : 12/5/2005<br>terry : 11/11/2005<br>mgross : 9/8/2005<br>mgross : 9/8/2005<br>alopez : 8/4/2005<br>terry : 8/3/2005<br>alopez : 4/22/2005<br>alopez : 4/22/2005<br>terry : 4/15/2005<br>carol : 3/4/2005<br>wwang : 3/2/2005<br>terry : 2/21/2005<br>terry : 8/17/2004<br>tkritzer : 5/28/2003<br>terry : 5/16/2003<br>cwells : 10/25/2002<br>tkritzer : 10/18/2002<br>tkritzer : 10/11/2002<br>tkritzer : 10/11/2002<br>mgross : 8/6/2002<br>mgross : 8/6/2002<br>ckniffin : 5/15/2002<br>carol : 1/8/2002<br>cwells : 10/9/2001<br>cwells : 10/5/2001<br>mcapotos : 6/7/2001<br>mcapotos : 6/5/2001<br>mcapotos : 6/4/2001<br>terry : 6/1/2001<br>mcapotos : 11/1/2000<br>mcapotos : 10/20/2000<br>alopez : 8/1/2000<br>carol : 5/25/2000<br>mgross : 3/9/2000<br>terry : 2/16/2000<br>alopez : 2/2/2000<br>terry : 2/1/2000<br>carol : 1/4/1999<br>terry : 12/30/1998<br>dkim : 9/11/1998<br>carol : 6/18/1998<br>alopez : 2/27/1998<br>terry : 2/27/1998<br>terry : 10/28/1997<br>alopez : 10/27/1997<br>terry : 10/22/1997<br>terry : 7/8/1997<br>terry : 6/23/1997<br>terry : 6/18/1997<br>randy : 8/31/1996<br>terry : 8/31/1996<br>mark : 3/15/1996<br>terry : 3/5/1996<br>mark : 2/5/1996<br>terry : 1/29/1996<br>carol : 12/7/1994<br>jason : 6/21/1994
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<h3>
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<span class="mim-font">
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<strong>*</strong> 156845
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTOR; MITF
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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MICROPHTHALMIA, MOUSE, HOMOLOG OF; MI
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MITF</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1332382002, 403805009;
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<strong>
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<em>
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Cytogenetic location: 3p13
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:69,739,464-69,968,332 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<span class="mim-font">
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3p13
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<span class="mim-font">
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{Melanoma, cutaneous malignant, susceptibility to, 8}
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<span class="mim-font">
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614456
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<span class="mim-font">
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</span>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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COMMAD syndrome
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<span class="mim-font">
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617306
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<span class="mim-font">
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Autosomal recessive
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</span>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Tietz albinism-deafness syndrome
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</span>
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<span class="mim-font">
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103500
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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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<span class="mim-font">
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3
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<span class="mim-font">
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Waardenburg syndrome, type 2A
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</td>
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<span class="mim-font">
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193510
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<span class="mim-font">
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Autosomal dominant
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</span>
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<span class="mim-font">
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3
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</table>
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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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<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>MITF is a basic helix-loop-helix (hHLH)-leucine zipper protein that plays a role in the development of various cell types, including neural crest-derived melanocytes and optic cup-derived retinal pigment epithelial cells (Fuse et al., 1999). </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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<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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<p>The mouse 'microphthalmia' (mi) gene encodes a bHLH zipper protein that functions as a homodimeric transcription factor. Mutations in mi lead to loss of pigmentation in the eye, inner ear, and skin, and to reduced eye size and early-onset deafness. Mice with mi mutations serve as models for human pigment disturbances in skin and eye that may be combined with sensorineural deafness. Tachibana et al. (1994) obtained cDNA and genomic clones of the human homolog of mouse mi, MITF, and identified a restriction fragment length polymorphism in the gene. The deduced mouse and human MITF proteins share 94.3% amino acid identity. Both proteins contain 419 amino acids and have central bHLH domains. </p><p>Fuse et al. (1999) noted that 3 different MITF splice variants, MITF-A, MITF-M, and MITF-H, had been identified. The variants differ in their 5-prime ends and encode proteins with different N termini. The deduced MITF-A, MITF-H, and MITF-M proteins have calculated molecular masses of 58.2, 56.4, and 46.9 kD, respectively. All MITF isoforms have a central transcriptional activation domain, followed by a bHLH-leucine zipper region and a C-terminal serine-rich region. MITF-M differs from the other isoforms in that it has a 6-amino acid insertion prior to the basic region. Fuse et al. (1999) cloned a novel MITF splice variant, MITF-C, by PCR and 5-prime RACE of a kidney cDNA library. The deduced MITF-C protein contains 519 amino acids and has a calculated molecular mass of 58.0 kD. Like the other MITF isoforms, MITF-C has a unique N terminus, and it does not have the 6-amino acid insertion found in MITF-M. RT-PCR detected coexpression of MITF-A and MITF-H in all human cell lines examined and in kidney, whereas MITF-M was detected only in melanoma cell lines. MITF-C was expressed in many cell lines, but not in melanomas. Western blot analysis of HeLa cells transfected with these 4 MITF variants revealed proteins that migrated at apparent molecular masses higher than their calculated molecular masses. </p><p>Udono et al. (2000) identified a novel MITF splice variant, MITF-B, that encodes a 495-amino acid protein with a calculated molecular mass of 55.4 kD. RT-PCR detected MITF-B expression in all cell types examined. </p>
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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>As mice with mutations at mi alleles and humans with WS2 lack melanocytes in affected tissues, Tachibana et al. (1996) speculated that MITF may be involved in mediating melanocyte differentiation by functioning as a transcription factor. In support of this idea, they demonstrated that NIH 3T3 cells transfected with MITF developed melanocytic phenotypes. MITF transfectants formed foci of morphologically altered cells, which resembled those induced by oncogenes, but did not exhibit malignant phenotypes. Instead, they contained dendritic cells that expressed melanogenic marker proteins such as tyrosinase and tyrosinase-related protein-1 (TYRP1; 115501). Such properties were not observed in cells transfected with the closely related TFE3 cDNA. </p><p>Mutations in MITF and PAX3, encoding transcription factors, are responsible for Waardenburg syndrome type 2A (WS2A; 193510) and WS1/WS3 (193500, 148820), respectively. Tachibana et al. (1996) showed that MITF transactivates the gene for tyrosinase (TYR; 606933), a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation in the skin, hair, and eyes, and hearing function in the cochlea. Therefore, hypopigmentation and hearing loss in WS2 are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations. However, the molecular mechanism by which PAX3 mutations cause the auditory-pigmentary symptoms in WS1/WS3 had not been explained. </p><p>Watanabe et al. (1998) showed that PAX3, a transcription factor with a paired domain and a homeodomain, transactivates the MITF promoter. They further showed that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain failed to recognize and transactivate the MITF promoter. These results provided evidence that PAX3 directly regulates MITF, and suggested that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1. </p><p>In mouse follicular melanocytes, production of eumelanins and pheomelanins is under the control of 2 intercellular signaling molecules that exert opposite actions: alpha-MSH (see 176830), which preferentially increases the synthesis of eumelanins, and agouti signal protein (ASP; 600201), whose expression favors the production of hair containing pheomelanins. Aberdam et al. (1998) reported that ASP not only affects mature melanocytes but can also inhibit the differentiation of melanoblasts. They showed that both alpha-MSH and forskolin promote the differentiation of murine melanoblasts into mature melanocytes, and that ASP inhibits this process. Expression of MITF and its binding to an M-box regulatory element is inhibited by ASP. Aberdam et al. (1998) also showed that in a murine melanoma cell line, ASP inhibits alpha-MSH-stimulated expression of tyrosinase (see 606933), TYRP1, and TYRP2 (DCT; 191275) through an inhibition of the transcriptional activity of their respective promoters. Further, ASP inhibits alpha-MSH-induced expression of the MITF gene and reduces the level of MITF in the cells. Aberdam et al. (1998) concluded that ASP can regulate both melanoblast differentiation and melanogenesis, pointing out the key role of MITF in the control of these processes. </p><p>Fuse et al. (1999) found that MITF-A, MITF-H, MITF-M, and MITF-C transactivated a tyrosinase test promoter in transfected HeLa cells. All tested isoforms, except MITF-C, also weakly transactivated a heme oxygenase-1 (HMOX1; 141250) test promoter. </p><p>Udono et al. (2000) showed that MITF-B transactivated the tyrosinase, TYRP1, and TYRP2 promoters. The ability of MITF-A, MITF-H, and MITF-M to transactivate promoter activity varied depending on the cell types assayed. </p><p>Takeda et al. (2000) demonstrated that serine at codon 298 plays an important role in MITF function. Glycogen synthase kinase-3B (GSK3B; 605004) was found to phosphorylate serine-298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter. Serine-298 was also phosphorylated in vivo, and expression of dominant-negative GSK3-beta selectively suppressed the ability of MITF to transactivate the tyrosinase promoter. </p><p>Khaled et al. (2002) found that GSK3B synergized with MITF in mouse melanoma cells to activate the tyrosinase promoter. Lithium, a GSK3B inhibitor, impaired the response of the tyrosinase promoter to cAMP, and cAMP increased binding of MITF to the M-box regulatory element. Khaled et al. (2002) concluded that activation of GSK3B by cAMP facilitates MITF binding to the tyrosinase promoter, stimulating melanogenesis. </p><p>Bondurand et al. (2000) showed that SOX10 (602229), in synergy with PAX3, strongly activates MITF expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in WS could explain the auditory/pigmentary symptoms of this disease. </p><p>The SOX10 and PAX3 transcription factors can directly regulate both MITF and RET in a synergistic fashion. Lang and Epstein (2003) showed that PAX3 and SOX10 can physically interact; this interaction contributes to synergistic activation of a conserved RET enhancer, and it explains why SOX10 mutants that cannot bind DNA still retain the ability to activate this enhancer in the presence of PAX3. However, in the context of the MITF gene, PAX3 and SOX10 must each bind independently to DNA in order to achieve synergy. These observations appear to explain the Waardenburg syndrome type 2E phenotype (WS2E; 611584) caused by a specific SOX10 mutation (602229.0005) in the HMG box that abrogates DNA binding without disrupting association with PAX3. </p><p>There is a phenotypic similarity between microphthalmia Mitf mi/mi mutant mice and cathepsin K (601105)-null mice as well as the human disease pycnodysostosis (265800) caused by cathepsin K deficiency. Cathepsin K is a cysteine protease from the papain family of proteases and plays an important role in osteoclast function. In mice, dominant-negative, but not recessive, mutations of Mitf produce osteopetrosis (see 166600), suggesting a functional requirement for other family members, such as TFE3 (314310), TFEB (600744), and TFEC (604732), which are potential dimerization partners. Motyckova et al. (2001) identified cathepsin K as a transcriptional target of MITF and TFE3 (314310) via 3 consensus elements in the cathepsin K promoter. Additionally, cathepsin K mRNA and protein were found to be deficient in Mitf mutant osteoclasts, and overexpression of wildtype Mitf dramatically upregulated the expression of endogenous cathepsin K in cultured human osteoclasts. Cathepsin K promoter activity was disrupted by dominant-negative, but not recessive, mouse alleles of Mitf in a pattern that closely matches their osteopetrotic phenotypes. This relationship between cathepsin K and the MITF family helps explain the phenotypic overlap of their corresponding deficiencies in pycnodysostosis and osteopetrosis and identifies likely regulators of cathepsin K expression in bone homeostasis and human malignancy. </p><p>To identify MITF-dependent KIT (164920) transcriptional targets in primary human melanocytes, microarray studies were undertaken by McGill et al. (2002). Among identified targets was BCL2 (151430), whose germline deletion produced melanocyte loss and exhibited phenotypic synergy with Mitf in mice. The regulation of BCL2 by MITF was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. MITF was found to regulate BCL2 in osteoclasts, and both Mitf mi/mi and Bcl2 -/- mice exhibited severe osteopetrosis. Disruption of MITF in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helped explain the vital roles of both MITF and BCL2 in the melanocyte lineage and the well-known treatment resistance of melanoma. </p><p>The Mitf-Tfe family of hHLH-leucine zipper (ZIP) translocation factors comprises 4 members: MITF, TFE3, TFEB (600744), and TFEC (604732). In vitro, each protein in the family can bind DNA as a homo- or heterodimer with other family members. Mutational studies in mice have shown that Mitf is essential for melanocyte and eye development consistent with the causation of a form of Waardenburg syndrome, whereas Tfeb is required for placenta vascularization. Steingrimsson et al. (2002) uncovered a role for Tfe3 in osteoclast development that is functionally redundant with that of Mitf. Although osteoclasts seem normal in Mitf or Tfe3 null mice, the combined loss of the 2 genes resulted in severe osteopetrosis. Steingrimsson et al. (2002) also showed that Tfec mutant mice were phenotypically normal, and that the Tfec mutation does not alter the phenotype of Mitf, Tfeb, or Tfe3 mutant mice. Their studies failed to identify any phenotypic overlap between the different Mitf-Tfe mutations. These results suggested that heterodimeric interactions are not essential for Mitf-Tfe function, in contrast to other bHLH-ZIP families like Myc/Max/Mad, where heterodimeric interactions seem to be essential. </p><p>Selzer et al. (2002) found that MITF-M was repressed in 8 of 14 established melanoma cell lines tested. Transfection of MITF-M into a melanoma cell line lacking the MITF-M isoform and into a permanent cell line established from normal melanocytes resulted in slower tumor growth. In addition to growth-inhibitory effects, MITF-M expression led to a change in the histopathologic appearance of tumors from epitheloid toward a spindle-cell type in vivo. These results indicated a role for the MITF-M isoform in the in vivo growth control and phenotype of melanoma. Thus, MITF-M may qualify as a marker capable of identifying subgroups of melanoma patients with different tumor biology and prognosis. </p><p>Widlund et al. (2002) identified beta-catenin (CTNNB1; 116806) as a significant regulator of melanoma cell growth, with MITF as a critical downstream target. Disruption of the canonical Wnt (see 164820) pathway abrogated growth of melanoma cells, and constitutive overexpression of MITF rescued the growth suppression. </p><p>Yasumoto et al. (2002) found that functional cooperation between MITF-M and LEF1 (153245) in several mammalian cell lines resulted in synergistic transactivation of the DCT promoter, an early melanoblast marker. Beta-catenin was required for efficient transactivation, but was dispensable for the interaction between MITF-M and LEF1. </p><p>Vetrini et al. (2004) identified an E-box MITF-M-binding element within the OA1 (GPR143; 300808) promoter. Using several in vitro and in vivo approaches, they confirmed that MTF-M bound the OA1 E-box and could drive expression of OA1 in human and mouse melanocytes and retinal pigment epithelium. </p><p>In addition to its role in melanocyte and melanoma survival and cell cycle progression, Carreira et al. (2005) showed that MITF can act as a novel antiproliferative transcription factor able to induce a G1 cell cycle arrest that is dependent on MITF-mediated activation of the p21(Cip1) (CDKN1A; 116899) cyclin-dependent kinase inhibitor gene. Moreover, cooperation between MITF and RB1 (614041) potentiates the ability of MITF to activate transcription. Carreira et al. (2005) suggested that MITF-mediated activation of p21(Cip1) expression and consequent hypophosphorylation of RB1 contributes to cell cycle exit and activation of the differentiation program. </p><p>Using human melanocytes and melanoma cell lines, Carreira et al. (2006) identified MITF as a regulator of DIA1 (DIAPH1; 602121), a protein that controls actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Since DIA1 also regulates SKP2 (601436), an F-box protein that promotes degradation of p27(Kip1) (CDKN1B; 600778), depletion of MITF led to downregulation of DIA1, followed by p27(Kip1)-dependent G1 arrest, reorganization of the actin cytoskeleton, and increased cellular invasiveness. In contrast, increased MITF expression promoted proliferation. Carreira et al. (2006) concluded that variations in environmental cues that determine MITF activity dictate the differentiation, proliferative, and invasive/migratory potential of melanoma cells. </p><p>By integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, Garraway et al. (2005) identified the melanocyte master regulator MITF as the target of a novel melanoma amplification. Garraway et al. (2005) found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF (164757) mutation and p16 (CDKN2A; 600160) inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF mutant (V600E; 164757.0001) transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Garraway et al. (2005) suggested that targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Garraway et al. (2005) concluded that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumor progression. </p><p>Larribere et al. (2005) found a role for MITF in apoptosis. They demonstrated that MITF is a caspase-3 (CASP3; 600636) substrate and cleavage of MITF within its C-terminal domain releases a proapoptotic C-terminal fragment. Expression of a noncleavable form of MITF rendered melanoma cells resistant to apoptotic stimuli. Using small interfering RNA directed against MITF, Larribere et al. (2005) found that downregulation of MITF alone did not induce apoptosis, but expression of the C-terminal fragment sensitized melanoma cells to apoptotic stimuli. </p><p>Loercher et al. (2005) showed that expression of MITF in mouse embryonic fibroblasts resulted in marked growth inhibition and morphologic changes consistent with melanocyte differentiation. MITF regulated cell cycle exit by activating the cell cycle inhibitor INK4A (CDKN2A). MITF bound the INK4A promoter, activated p16(INK4A) mRNA and protein expression, and induced RB1 protein hypophosphorylation, thereby triggering cell cycle arrest. Activation of INK4A was required for efficient melanocyte differentiation, and MITF was required to maintain INK4A expression in mature melanocytes. </p><p>Using a reporter gene assay, Bemis et al. (2008) identified a functional microRNA-137 (MIR137; 614304)-binding site in the 3-prime UTR of the MITF transcript. They also identified a variable nucleotide tandem repeat (VNTR) in the 5-prime region of the MIR137 gene that appeared to influence MIR137 expression. In cell lines with 12 VNTRs in this region, the primary MIR137 transcript had an altered secondary structure and was inefficiently processed to mature MIR137, leading to inefficient MITF downregulation. In contrast, cell lines with only 3 VNTRs upstream of MIR137 showed efficient downregulation of MITF expression. </p><p>Segura et al. (2009) identified FOXO3 (602681) and MITF as putative targets of MIR182 (611607) and showed that expression of MIR182 inversely correlated with FOXO3 and MITF levels in metastatic melanomas. MIR182 overexpression promoted migration and survival by direct repression of FOXO3 and MITF. </p><p>The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. Perera et al. (2015) showed that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins (MITF; TFE3, 314310; and TFEB, 600744) are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling revealed that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. Perera et al. (2015) concluded that their results identified the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrated that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy. </p><p>Using mouse and human mast cells and rat basophil leukemia (RBL) cells, Sharkia et al. (2017) showed that inhibition of pyruvate dehydrogenase (PDH; see 300502) decreased degranulation and cytokine secretion. In mice, PDH inhibition decreased histamine secretion and lung resistance, but not airway inflammation. Yeast 2-hybrid, immunoprecipitation, and Western blot analyses showed that mouse Mitf interacted with the E1 subunit of PDH and that this interaction occurred after immunologic activation. Western blot, cell fractionation, and flow cytometric analyses demonstrated localization of Mitf to mitochondria. Overexpression of Mitf or Mitf lacking the leucine zipper domain resulted in decreased PDH activity, increased pyruvate activity, and reduced ATP and oxygen consumption levels in RBL cells. Sharkia et al. (2017) concluded that association of MITF with PDH is an important regulator of mast cell function. </p>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Tassabehji et al. (1994) demonstrated that the human MITF gene has 9 exons. </p><p>Udono et al. (2000) determined that the MITF gene contains 12 exons. The first 4 exons are differentially spliced to encode the unique N termini of the MITF isoforms. All MITF variants contain 8 common downstream exons. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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<span class="mim-text-font">
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<p>By somatic cell hybrid studies and fluorescence in situ hybridization, Tachibana et al. (1994) mapped the human MITF gene to a region of chromosome 3 that shows a disrupted syntenic conservation with the region on mouse chromosome 6 to which mi maps, namely, 3p14.1-p12.3. As the human MITF gene was found to reside on chromosome 3, Tachibana et al. (1994) suggested that it may be involved in cases of Waardenburg syndrome type 2 that do not show linkage to the PAX3 (606597) locus on chromosome 2. The ermine phenotype, or BADS syndrome (227010), was also mentioned as a possible homolog. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Waardenburg Syndrome Type 2A</em></strong></p><p>
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Tassabehji et al. (1994) demonstrated mutations in the MITF gene in affected individuals in 2 families segregating Waardenburg syndrome type 2A (WS2A; 193510). Both mutations affected splice sites in the MITF gene. One might expect that the MITF mutations would result in abnormal proteins which, when combined with the normal protein, would make dysfunctional dimers. Neither of the mutations appeared to function in that way, and Tassabehji et al. (1994) suggested possible explanations. They also pointed out that Waardenburg syndrome type II is relatively ill-defined, since hearing loss is not universal and the distinction in families with dominant white forelock or dominant heterochromia is often not clear. Furthermore, there are families in which unaffected but sometimes consanguineous parents have children with pigmentary disturbances sometimes combined with hearing loss and/or Hirschsprung disease. In the case of these apparently recessive syndromes, MITF was considered a good candidate for the mutant gene. </p><p>Tassabehji et al. (1995) concluded that Waardenburg syndrome type II is heterogeneous, with about 20% of cases caused by mutations in MITF. In the mouse, mi mutations can be dominant or recessive. Dominant alleles are believed to work by a dominant-negative effect. A protein with intact helix-loop-helix and zipper sequences but defective DNA binding or transactivation domains sequesters the normal gene products in inactive dimers. Mutations that prevent dimerization are recessive. Tassabehji et al. (1995) noted that most of the mouse mutations are recessive and most of the human mutations in MITF appear to be dominant. They concluded that MITF is another example of a gene like RET (164761) or PAX3 in which humans are more sensitive than mice to gene dosage effects in heterozygotes. </p><p><strong><em>Tietz Albinism-Deafness Syndrome</em></strong></p><p>
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In a family with partial albinism and sensorineural deafness (Tietz albinism-deafness syndrome, TADS; 103500), Tassabehji et al. (1995) identified the exact equivalent of the mouse microphthalmia mutation, namely a deletion of 1 of a run of 4 arginines in the basic domain (R217del; 156845.0003). </p><p>In affected members of the family with hypopigmentation and deafness reported by Tietz (1963), Smith et al. (2000) identified a mutation in the MITF gene (156845.0006). </p><p>In a 24-year-old woman with Tietz syndrome, Izumi et al. (2008) identified heterozygosity for the R217del mutation in the MITF gene. </p><p><strong><em>Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness</em></strong></p><p>
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In 2 unrelated children with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306), whose parents exhibited features of WS2A, George et al. (2016) identified compound heterozygosity for mutations in the MITF gene (156845.0003 and 156845.0010-156845.0012). The parents in both families were each heterozygous for 1 of the mutations, as were the probands' sibs who showed features similar to those in the parents. </p><p><strong><em>Cutaneous Malignant Melanoma 8, Susceptibility to</em></strong></p><p>
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Bertolotto et al. (2011) identified a missense mutation in MITF (E318K; 156845.0009) that greatly increases the risk of malignant melanoma and/or renal cell carcinoma in carriers, with an odds ratio of 14.46 (95% CI 3.74-48.04) for the risk of melanoma plus renal cell carcinoma. Yokoyama et al. (2011) independently identified the E318K mutation in the MITF gene as increasing the risk of melanoma in both families and sporadic cases. The variant cosegregated with melanoma in some, but not all, cases of melanoma in the initial family identified, but linkage analysis of 31 families subsequently identified to carry the variant generated a lod score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case control sample. Likewise, it was similarly associated in an independent case control sample from the United Kingdom. Yokoyama et al. (2011) also showed that E318K prevents MITF sumoylation and results in differential expression of MITF target genes. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Steingrimsson et al. (1994) characterized the molecular defects associated with 8 murine mi mutations, which vary both in their mode of inheritance and in the cell types they affect. These molecular data provided insight into the phenotypic and developmental consequences of mi mutations and offered a mouse model for WS2. Jackson and Raymond (1994) and Moore (1995) provided commentaries. </p><p>The anophthalmic white (Wh) mutation in Syrian hamsters causes pigmentation abnormalities and variable hearing loss in heterozygotes and absence of pigmentation, profound deafness, and severe eye reduction in homozygotes. Hodgkinson et al. (1998) determined that the Wh phenotype is caused by a nonsense mutation in the hamster Mitf gene that truncates the protein between helices 1 and 2 of the DNA-binding and dimerization domain. The mRNA is destabilized, and the protein is unable to dimerize or bind DNA target sites. The mutant protein does not act through a dominant-negative mechanism, and the Wh mutation is inherited as a semidominant trait. </p><p>Thaung et al. (2002) carried out a genomewide screen for novel N-ethyl-N-nitrosourea-induced mutations that give rise to eye and vision abnormalities in the mouse, and identified 25 inherited phenotypes that affect all parts of the eye. A combination of genetic mapping, complementation, and molecular analysis revealed that 14 of these were mutations in genes previously identified to play a role in eye pathophysiology, namely Pax6 (607108), Mitf, Egfr (131550), and Pde6b (180072). Many of the others were located in genomic regions lacking candidate genes. </p><p>Using PCR, Western blot, and immunohistochemical analyses, Tshori et al. (2006) found that Mitf was expressed in cardiomyocytes from wildtype mice, but not in tg/tg mice, which have a 50-copy insertion of a transgene in the Mitf promoter region. The ratio of heart weight to body weight was reduced in tg/tg mice and ce/ ce mice, which lack the Zip domain of the Mitf protein. In response to beta-adrenergic stimulation, the Mitf mutant mouse strains had reduced hypertrophic responses and did not produce increased levels of Bnp (NPPB; 600295). Tshori et al. (2006) concluded that MITF plays an essential role in beta-adrenergic-induced cardiac hypertrophy. </p><p>George et al. (2016) expressed 2 human MITF mutations, R318del (156845.0003) and K307N (156845.0010), in 1-cell-stage zebrafish embryos and quantified melanocytes in the dorsal-trunk region at 34 to 36 hours postfertilization. Both mutations resulted in significantly lower numbers of melanocytes compared to controls. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<h4>
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<span class="mim-font">
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<strong>.0001 WAARDENBURG SYNDROME, TYPE 2A</strong>
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</span>
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</h4>
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MITF, IVS1DS, G-A, +1
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<br />
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SNP: rs1553701477,
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ClinVar: RCV000015340
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<span class="mim-text-font">
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<p>In a family with type II Waardenburg syndrome (WS2A; 193510) that showed linkage to markers on 3p in the vicinity of the MITF gene, Tassabehji et al. (1994) found that amplified DNA of exon 1 showed an abnormal band on SSCP/heteroduplex analysis. Sequencing demonstrated a GT-to-AT change, which would abolish the donor splice site at the end of exon 1. Two individuals were clinically ambiguous because one had hearing loss, which might have been attributable to a head injury, and the second had minor heterochromia as his only feature of Waardenburg syndrome. By linkage analysis and direct mutation testing, however, both of these individuals carried the MITF mutation. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 WAARDENBURG SYNDROME, TYPE 2A</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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MITF, IVS4AS, A-C, -2
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<br />
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SNP: rs1553703612,
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ClinVar: RCV000015341
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a family with type 2A Waardenburg syndrome (WS2A; 193510) showing linkage to markers on 3p in the vicinity of the MITF locus, Tassabehji et al. (1994) found that all affected members showed an abnormal SSCP band in amplified exon 5. Sequencing demonstrated that the AG acceptor splice site at the end of intron 4 had been mutated to CG. </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 TIETZ ALBINISM-DEAFNESS 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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COLOBOMA, OSTEOPETROSIS, MICROPHTHALMIA, MACROCEPHALY, ALBINISM, AND DEAFNESS, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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MITF, 3-BP DEL, ARG217DEL
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<br />
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SNP: rs1553704814,
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ClinVar: RCV000015342, RCV000498643, RCV000826199, RCV001290155, RCV001785452, RCV005222684
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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 family with partial albinism and sensorineural deafness (TADS; 103500), Tassabehji et al. (1995) identified the exact equivalent of the mouse microphthalmia mutation, namely a deletion of 1 of a run of 4 arginines in the basic domain. Following the mouse precedent, they labeled this mutation R217del, although from the DNA and protein sequences one could not say which of the 4 arginines was deleted. Amiel et al. (1998) noted that although the affected mother and son fulfilled diagnostic criteria for Waardenburg syndrome type 2 (see 193510), they more closely resembled the family reported by Tietz (1963). </p><p>In a 24-year-old woman with Tietz syndrome, Izumi et al. (2008) identified heterozygosity for the R217del mutation in the MITF gene. The authors noted that dimerization between mutant and wildtype protein would reduce the number of intact wildtype dimers with access to the nucleus to 25% of normal. Histologic examination of skin biopsy specimens revealed the presence of melanocytes, suggesting that the migration of melanocyte stem cells from the neural crest to the epidermal layer occurred normally. In the hypopigmented regions, however, a reduction in the number of melanosomes in keratinocytes adjacent to the melanocytes suggested a disruption in the transfer of melanosomes from the melanocytes to the keratinocytes; and in the hyperpigmented regions, an increase in the number of melanosomes in the keratinocytes adjacent to HMB45-positive melanocytes pointed to a high level of melanogenesis. </p><p>In a 5-year-old boy with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306), George et al. (2016) identified compound heterozygosity for mutations in the MITF gene: the first was a 3-bp deletion (c.952_954delAGA), which they stated corresponded to Arg318del in the MITF-A isoform and to Arg217del in the MITF-M isoform; the second was a c.921G-C transversion, resulting in a lys307-to-asn (K307N; 156845.0010) substitution in isoform MITF-A. The proband's parents and 1 brother, who exhibited features of WS2A, were each heterozygous for 1 of the mutations. The K307N mutation was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. Functional analysis showed that, unlike wildtype MITF, the R318del mutant did not migrate to the nucleus in transfected HEK293 cells or bind consensus M-box or E-box DNA sequences in vitro; in addition, this allele did not activate the tyrosinase (TYR; 606933) promoter or repress the FGF19 (603891) promoter in dual luciferase reporter assays. In comparison, the K307N allele was distributed equally between the nucleus and the cytoplasm and exhibited approximately 20% of the DNA-binding capability of wildtype MITF, but had significant transcriptional regulatory potential on TYR and FGF19 promoters. Coexpression of R318del and K307N in HEK293 cells resulted in migration of only 30% of MITF into the nucleus, whereas coexpression of mutant with wildtype protein resulted in 36% or 81% migration, respectively. DNA binding of co-in-vitro-translated R318del and K307N was less than 20% of that of wildtype MITF for consensus E-box and M-box elements; wildtype with R318del resulted in approximately 50% reduction of DNA binding, whereas wildtype with K307N bound both consensus elements better than wildtype. Transcriptional activation of the TYRP1 (115501) promoter was reduced more dramatically when increasing amounts of R318del were coexpressed with K307N than with wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 WAARDENBURG SYNDROME, TYPE 2A</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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MITF, SER250PRO
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<br />
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SNP: rs104893744,
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ClinVar: RCV000015343
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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 their family WS.115 with Waardenburg syndrome (WS2A; 193510), Tassabehji et al. (1995) identified a T-to-C mutation which changed codon 250 from TCC (ser) to CCC (pro). The patient was a woman with unilateral hearing loss and premature graying who had a son with unilateral hearing loss. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 WAARDENBURG SYNDROME, TYPE 2A</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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MITF, 1-BP DEL
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<br />
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SNP: rs1553705282,
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ClinVar: RCV000015344
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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>Morell et al. (1997) described apparent digenic inheritance of the combination of Waardenburg syndrome type II (WS2A; 193510) and ocular albinism. In a family originally reported by Bard (1978), Morell et al. (1997) found that affected individuals were heterozygous for a 1-bp deletion in codon 275 in exon 8 of the MITF gene, resulting in a frameshift and a TGA termination codon in exon 9. The affected individuals were also either homozygous or heterozygous for the arg402-to-gln polymorphism (R402Q) of the tyrosinase gene (TYR; 606933.0009). TYR gene expression is controlled by the MITF transcription factor. </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>.0006 TIETZ ALBINISM-DEAFNESS 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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MITF, ASN210LYS
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<br />
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SNP: rs104893745,
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ClinVar: RCV000015345
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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>Smith et al. (2000) restudied the family with hypopigmentation and deafness (TADS; 103500) reported by Tietz (1963) and confirmed the existence of the syndrome through at least 4 generations. All affected individuals were born 'snow white,' but gradually gained some pigmentation, with fair skin and blond hair. Eyebrows and eyelashes remained blond. Hearing loss was always bilateral, congenital, and profound, and communication was primarily through signing. There was no variation in expression and penetrance was complete. Linkage to the region of MITF was demonstrated in the family and a unique heteroduplex pattern of exons 5 and 6 of MITF was found to segregate with affected members of the kindred. The change bordering exon 5 was adjacent to the splice junction consensus sequence. The change in exon 6 resulted in an asn210-to-lys amino acid substitution in the basic region of the transcription factor. </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>
|
|
<span class="mim-font">
|
|
<strong>.0007 WAARDENBURG SYNDROME, TYPE 2A</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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MITF, ARG214TER
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<br />
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SNP: rs104893746,
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ClinVar: RCV000015346, RCV000414854, RCV000415265, RCV001200166, RCV001813988
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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>Lalwani et al. (1998) reported a 3-generation Indian family with a point mutation in the MITF gene causing Waardenburg syndrome type 2A (WS2A; 193510). Mutation screening of the MITF gene showed a 760C-T transition resulting in an arg214-to-ter nonsense mutation, predicted to result in a truncated MITF protein. The mutation occurred in a CpG dinucleotide. The R214X mutation was reported earlier in a northern European family by Nobukuni et al. (1996). Comparison of the phenotype of the 2 families demonstrated a significant difference in pigmentary disturbance of the eye. In both families, hearing loss was the most common finding, followed by ocular pigmentary disturbance. Heterochromia iridis occurred in 8 of 11 affected members of the Indian family and in 4 of 14 affected members of the European family. </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>
|
|
<span class="mim-font">
|
|
<strong>.0008 WAARDENBURG SYNDROME, TYPE 2A</strong>
|
|
</span>
|
|
</h4>
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|
</div>
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<div>
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<span class="mim-text-font">
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MITF, SER298PRO
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<br />
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SNP: rs104893747,
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gnomAD: rs104893747,
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ClinVar: RCV000015347, RCV001541066, RCV002281708, RCV002513060, RCV003974827, RCV004786263
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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>Tassabehji et al. (1995) found that affected members of a family with type 2 Waardenburg syndrome (WS2A; 193510) had a ser298-to-pro substitution in their MITF gene. Takeda et al. (2000) showed that ser298, which is located downstream of the basic helix-loop-helix leucine zipper, plays an important role in MITF function. They found that glycogen synthase kinase-3 (GSK3) phosphorylated ser298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter. The same serine was found to be phosphorylated in vivo, and expression of dominant-negative GSK3-beta selectively suppressed the ability of MITF to transactivate the tyrosinase promoter. Moreover, mutation of ser298 disabled phosphorylation of MITF by GSK3-beta and impaired MITF function. </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>
|
|
<span class="mim-font">
|
|
<strong>.0009 MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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MITF, GLU318LYS
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<br />
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|
|
SNP: rs149617956,
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|
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|
|
gnomAD: rs149617956,
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|
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|
|
ClinVar: RCV000022661, RCV000129682, RCV000222278, RCV000484916, RCV000627790, RCV001195106, RCV001535706, RCV002247378, RCV002490402
|
|
|
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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>Bertolotto et al. (2011) identified a c.952G-A transition (c.952G-A, NM_000248.3) in the MITF gene (isoform MITF-M), resulting in a glu-to-lys substitution at codon 318 (E318K). This missense mutation was found at increased frequency in the germline of individuals with melanoma or renal cell carcinoma and at much increased frequency in individuals with both melanoma and renal cell carcinoma compared with controls. The overall allele frequency in controls was 0.003, in patients with melanoma and/or renal cell carcinoma it was 0.016, and among individuals with both melanoma and renal cell carcinoma it was 0.040. </p><p>Yokoyama et al. (2011) independently identified the E318K mutation in the MITF gene (isoform MITF-M) as increasing the risk of melanoma in both families and sporadic cases. The variant cosegregated with melanoma in some, but not all, cases of melanoma in the initial family identified, but linkage analysis of 31 families subsequently identified to carry the variant generated a lod score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. Yokoyama et al. (2011) also showed that E318K prevents MITF sumoylation and results in differential expression of MITF target genes. </p>
|
|
</span>
|
|
</div>
|
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|
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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>.0010 COLOBOMA, OSTEOPETROSIS, MICROPHTHALMIA, MACROCEPHALY, ALBINISM, AND DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
WAARDENBURG SYNDROME, TYPE 2A, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MITF, LYS307ASN
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|
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|
|
|
<br />
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|
|
|
SNP: rs1057519325,
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|
|
|
|
|
|
|
ClinVar: RCV000416286, RCV000416300
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.921G-C transversion (c.921G-C, NM_198159.2) in the MITF gene (isoform MITF-A), resulting in a lys307-to-asn (K307N) substitution, that was found in compound heterozygous state in a 5-year-old boy with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306) by George et al. (2016), see 156845.0003. The proband's mother, who exhibited features of Waardenburg syndrome type 2A (WS2A; 193510), was heterozygous for the K307N mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 COLOBOMA, OSTEOPETROSIS, MICROPHTHALMIA, MACROCEPHALY, ALBINISM, AND DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
WAARDENBURG SYNDROME, TYPE 2A, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MITF, ARG318GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519326,
|
|
|
|
|
|
|
|
ClinVar: RCV000416288, RCV000416308
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 9-month-old girl with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306), George et al. (2016) identified compound heterozygosity for mutations in the MITF gene (MITF-A isoform): the first was a c.952A-G transition (c.952A-G, NM_198159.2), resulting in an arg318-to-gly (R318G) substitution; the second was a splice site mutation (c.938-1G-A), predicted to result in a premature termination codon (Leu312fsTer11; 156845.0012). The proband's parents and 3 sibs, who exhibited features of Waardenburg syndrome type 2A (WS2A; 193510), were each heterozygous for 1 of the mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 COLOBOMA, OSTEOPETROSIS, MICROPHTHALMIA, MACROCEPHALY, ALBINISM, AND DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
WAARDENBURG SYNDROME, TYPE 2A, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MITF, 938-1G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519327,
|
|
|
|
|
|
|
|
ClinVar: RCV000416298, RCV000416310, RCV003766173
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.938-1G-A transition (c.938-1G-A, NM_198159.2) in the MITF gene (MITF-A isoform), predicted to result in a premature termination codon (Leu312fsTer11), that was found in compound heterozygous state in a 9-month-old girl with COMMAD (617306) by George et al. (2016), see 156845.0011. The proband's mother, who exhibited features of Waardenburg syndrome type 2A (WS2A; 193510), was heterozygous for the splice site mutation. </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>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<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">
|
|
Aberdam, E., Bertolotto, C., Sviderskaya, E. V., de Thillot, V., Hemesath, T. J., Fisher, D. E., Bennett, D. C., Ortonne, J.-P., Ballotti, R.
|
|
<strong>Involvement of microphthalmia in the inhibition of melanocyte lineage differentiation and of melanogenesis by agouti signal protein.</strong>
|
|
J. Biol. Chem. 273: 19560-19565, 1998.
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|
[PubMed: 9677380]
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[Full Text: https://doi.org/10.1074/jbc.273.31.19560]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Amiel, J., Watkin, P. M., Tassabehji, M., Read, A. P., Winter, R. M.
|
|
<strong>Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome).</strong>
|
|
Clin. Dysmorph. 7: 17-20, 1998.
|
|
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[PubMed: 9546825]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bard, L. A.
|
|
<strong>Heterogeneity in Waardenburg's syndrome: report of a family with ocular albinism.</strong>
|
|
Arch. Ophthal. 96: 1193-1198, 1978.
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|
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|
[PubMed: 666627]
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[Full Text: https://doi.org/10.1001/archopht.1978.03910060027006]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bemis, L. T., Chen, R., Amato, C. M., Classen, E. H., Robinson, S. E., Coffey, D. G., Erickson, P. F., Shellman, Y. G., Robinson, W. A.
|
|
<strong>MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines.</strong>
|
|
Cancer Res. 68: 1362-1368, 2008.
|
|
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|
|
[PubMed: 18316599]
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|
[Full Text: https://doi.org/10.1158/0008-5472.CAN-07-2912]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bertolotto, C., Lesueur, F., Giuliano, S., Strub, T., de Lichy, M., Bille, K., Dessen, P., d'Hayer, B., Mohamdi, H., Remenieras, A., Maubec, E., de la Fouchardiere, A., and 45 others.
|
|
<strong>A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.</strong>
|
|
Nature 480: 94-98, 2011. Note: Erratum: Nature 531: 126 only, 2016.
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|
[PubMed: 22012259]
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[Full Text: https://doi.org/10.1038/nature10539]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M.
|
|
<strong>Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.</strong>
|
|
Hum. Molec. Genet. 9: 1907-1917, 2000.
|
|
|
|
|
|
[PubMed: 10942418]
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[Full Text: https://doi.org/10.1093/hmg/9.13.1907]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Carreira, S., Goodall, J., Aksan, I., La Rocca, S. A., Galibert, M.-D., Denat, L., Larue, L., Goding, C. R.
|
|
<strong>Mitf cooperates with Rb1 and activates p21(Cip1) expression to regulate cell cycle progression.</strong>
|
|
Nature 433: 764-769, 2005.
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|
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|
|
|
[PubMed: 15716956]
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|
|
[Full Text: https://doi.org/10.1038/nature03269]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Carreira, S., Goodall, J., Denat, L., Rodriguez, M., Nuciforo, P., Hoek, K. S., Testori, A., Larue, L., Goding, C. R.
|
|
<strong>Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.</strong>
|
|
Genes Dev. 20: 3426-3439, 2006.
|
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|
|
[PubMed: 17182868]
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[Full Text: https://doi.org/10.1101/gad.406406]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fuse, N., Yasumoto, K., Takeda, K., Amae, S., Yoshizawa, M., Udono, T., Takahashi, K., Tamai, M., Tomita, Y., Tachibana, M., Shibahara, S.
|
|
<strong>Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus.</strong>
|
|
J. Biochem. 126: 1043-1051, 1999.
|
|
|
|
|
|
[PubMed: 10578055]
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|
[Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a022548]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Watanabe, A., Takeda, K., Ploplis, B., Tachibana, M.
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<strong>Epistatic relationship between Waardenburg syndrome genes MITF and PAX3.</strong>
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Widlund, H. R., Horstmann, M. A., Price, E. R., Cui, J., Lessnick, S. L., Wu, M., He, X., Fisher, D. E.
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Yasumoto, K., Takeda, K., Saito, H., Watanabe, K., Takahashi, K., Shibahara, S.
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<strong>Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling.</strong>
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Yokoyama, S., Woods, S. L., Boyle, G. M., Aoude, L. G., MacGregor, S., Zismann, V., Gartside, M., Cust, A. E., Haq, R., Harland, M., Taylor, J. C., Duffy, D. L., and 35 others.
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<strong>A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.</strong>
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Paul J. Converse - updated : 08/15/2017<br>Marla J. F. O'Neill - updated : 01/23/2017<br>Ada Hamosh - updated : 09/11/2015<br>Ada Hamosh - updated : 1/4/2012<br>Patricia A. Hartz - updated : 11/8/2011<br>Patricia A. Hartz - updated : 1/20/2010<br>Marla J. F. O'Neill - updated : 5/7/2009<br>Patricia A. Hartz - updated : 3/2/2007<br>Paul J. Converse - updated : 1/5/2007<br>Marla J. F. O'Neill - updated : 10/13/2006<br>Patricia A. Hartz - updated : 11/11/2005<br>Patricia A. Hartz - updated : 9/8/2005<br>Ada Hamosh - updated : 8/3/2005<br>Ada Hamosh - updated : 4/15/2005<br>George E. Tiller - updated : 2/21/2005<br>Victor A. McKusick - updated : 5/16/2003<br>George E. Tiller - updated : 10/25/2002<br>Victor A. McKusick - updated : 10/11/2002<br>Stylianos E. Antonarakis - updated : 8/6/2002<br>Michael J. Wright - updated : 10/5/2001<br>Victor A. McKusick - updated : 6/1/2001<br>George E. Tiller - updated : 10/20/2000<br>Ada Hamosh - updated : 8/1/2000<br>Victor A. McKusick - updated : 2/16/2000<br>Ada Hamosh - updated : 2/1/2000<br>Victor A. McKusick - updated : 12/30/1998<br>Victor A. McKusick - updated : 2/27/1998<br>Victor A. McKusick - updated : 10/22/1997<br>Victor A. McKusick - updated : 6/23/1997
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Victor A. McKusick : 6/21/1994
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