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Entry
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- *601653 - EYA TRANSCRIPTIONAL COACTIVATOR AND PHOSPHATASE 1; EYA1
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- OMIM
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<p>
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<span class="h4">*601653</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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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/601653">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li 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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<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-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=ENSG00000104313;t=ENST00000340726" 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=2138" 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=601653" 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 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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<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=ENSG00000104313;t=ENST00000340726" 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_000503,NM_001288574,NM_001288575,NM_001370333,NM_001370334,NM_001370335,NM_001370336,NM_001411797,NM_172058,NM_172059,NM_172060,XM_011517484,XM_017013202,XM_017013208,XM_017013213,XM_047421519,XM_047421520,XM_047421521,XM_047421522,XM_047421523,XM_047421524,XM_047421525,XM_047421526,XM_047421527,XM_047421528,XM_047421529,XM_047421530" 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_000503" 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=601653" 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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<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=03388&isoform_id=03388_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/EYA1" 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/1834487,2661375,2664187,3183005,18479140,19923100,26667216,26667222,71360878,71360880,112292448,112292482,119607379,119607380,119607381,119607382,119607383,119607384,119607385,119607386,193785420,194381472,568384802,568384804,1034659591,1034659595,1034659606,1034659616,1278992422,1634229796,1634229825,1634229863,1634229867,2217371235,2217371237,2217371239,2217371242,2217371244,2217371247,2217371249,2217371251,2217371253,2217371255,2217371257,2217371259,2294430527,2462618382,2462618384,2462618386,2462618389,2462618391,2462618393,2462618395,2462618397,2462618400,2462618402,2462618404,2462618406,2462618408,2462618410,2462618412,2462618454" 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/Q99502" 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=2138" 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=ENSG00000104313;t=ENST00000340726" 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=EYA1" 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=EYA1" 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+2138" 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/EYA1" 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:2138" 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/2138" 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=chr8&hgg_gene=ENST00000340726.8&hgg_start=71197433&hgg_end=71548094&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:3519" 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:3519" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/eya1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601653[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=601653[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/EYA1/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/ENSG00000104313" 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=EYA1" 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=EYA1" 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=EYA1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EYA1&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/PA27931" 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:3519" 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/FBgn0000320.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:109344" 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/EYA1#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:109344" 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/2138/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2138" 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=WBGene00001377;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-990712-18" 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:2138" 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=EYA1&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> 429448005<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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601653
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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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EYA TRANSCRIPTIONAL COACTIVATOR AND PHOSPHATASE 1; EYA1
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
EYES ABSENT 1<br />
|
|
EYES ABSENT, DROSOPHILA, HOMOLOG OF, 1
|
|
</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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EYA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EYA1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/8/335?start=-3&limit=10&highlight=335">8q13.3</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:71197433-71548094&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'})">8:71,197,433-71,548,094</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=166780,602588,602588,113650" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/335?start=-3&limit=10&highlight=335">
|
|
8q13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Otofaciocervical syndrome
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/166780"> 166780 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<p>Members of the EYA family, including EYA1, have protein phosphatase function, and EYA enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation (summary by <a href="#17" class="mim-tip-reference" title="Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G. <strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong> Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628042</a>] [<a href="https://doi.org/10.1038/nature02083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628042">Li et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By positional cloning in the 8q13.3 region where the branchiootorenal dysplasia syndrome (BOR; <a href="/entry/113650">113650</a>) maps, <a href="#2" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. <strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong> Nature Genet. 15: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>] [<a href="https://doi.org/10.1038/ng0297-157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020840">Abdelhak et al. (1997)</a> identified a gene that they showed to be responsible for the disorder. The gene is a human homolog of the Drosophila 'eyes absent' gene (Eya) and was therefore called EYA1. The gene encodes a deduced 559-amino acid polypeptide with a predicted molecular mass of 61.2 kD. <a href="#2" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. <strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong> Nature Genet. 15: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>] [<a href="https://doi.org/10.1038/ng0297-157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020840">Abdelhak et al. (1997)</a> also found a highly conserved 271-amino acid C-terminal region in the products of 2 other human genes, which were subsequently called EYA2 (<a href="/entry/601654">601654</a>) and EYA3 (<a href="/entry/601655">601655</a>), demonstrating the existence of a novel gene family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G. <strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong> Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628042</a>] [<a href="https://doi.org/10.1038/nature02083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628042">Li et al. (2003)</a> showed that EYA1 encodes a dual-function transcription factor with an N-terminal transcriptional coactivator region and a C-terminal dephosphorylation domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. <strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong> Nature Genet. 15: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>] [<a href="https://doi.org/10.1038/ng0297-157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020840">Abdelhak et al. (1997)</a> studied the expression pattern of the mouse EYA1 ortholog and obtained results suggesting a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern indicated a role for Eya1 in the metanephric cells surrounding the 'just-divided' ureteric branches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#32" class="mim-tip-reference" title="Xu, P.-X., Cheng, J., Epstein, J. A., Maas, R. L. <strong>Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function.</strong> Proc. Nat. Acad. Sci. 94: 11974-11979, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342347</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342347[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.22.11974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9342347">Xu et al. (1997)</a> showed that in the limbs of 10.5-day mouse embryos, Eya1 expression was largely restricted to the flexor tendons, whereas Eya2 (<a href="/entry/601654">601654</a>) was expressed in the extensor tendons and probably also in the ligaments of the phalanges. They demonstrated that the proline/serine/threonine-rich N-terminal regions of the protein products of the Eya1, Eya2, and Eya3 (<a href="/entry/601655">601655</a>) genes have transcriptional activator activity. These results supported a role for the Eya genes in connective tissue patterning in the limbs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9342347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Azuma, N., Hirakiyama, A., Inoue, T., Asaka, A., Yamada, M. <strong>Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.</strong> Hum. Molec. Genet. 9: 363-366, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655545</a>] [<a href="https://doi.org/10.1093/hmg/9.3.363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655545">Azuma et al. (2000)</a> stated that in Drosophila, the Eya gene is involved in the formation of compound eyes. Flies with loss-of-function mutations of this gene develop no eyes and form ectopic eyes in the antennae and the ventral zone of the head on target expression. A highly conserved homologous gene in various invertebrates and vertebrates has been shown to function in the formation of the eye. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 sequence analysis, <a href="#12" class="mim-tip-reference" title="Hsiao, F. C., Williams, A., Davies, E. L., Rebay, I. <strong>Eyes absent mediates cross-talk between retinal determination genes and the receptor tyrosine kinase signaling pathway.</strong> Dev. Cell 1: 51-61, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11703923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11703923</a>] [<a href="https://doi.org/10.1016/s1534-5807(01)00011-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11703923">Hsiao et al. (2001)</a> identified 2 conserved mitogen-activated protein kinase (MAPK) sites in the EYA1 sequence. In vivo genetic analysis, together with in vitro kinase assay results, demonstrated that Eya is a substrate for extracellular signal-regulated kinase, the MAPK acting downstream in the receptor tyrosine kinase (RTK) signaling pathway. <a href="#12" class="mim-tip-reference" title="Hsiao, F. C., Williams, A., Davies, E. L., Rebay, I. <strong>Eyes absent mediates cross-talk between retinal determination genes and the receptor tyrosine kinase signaling pathway.</strong> Dev. Cell 1: 51-61, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11703923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11703923</a>] [<a href="https://doi.org/10.1016/s1534-5807(01)00011-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11703923">Hsiao et al. (2001)</a> hypothesized that phosphorylation of Drosophila Eya provides a direct regulatory link between the RTK/Ras/MAPK signaling cascade and the retinal determination gene network. They concluded that Eya function in Drosophila is positively regulated by MAPK-mediated phosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11703923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Buller, C., Xu, X., Marquis, V., Schwanke, R., Xu, P.-X. <strong>Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.</strong> Hum. Molec. Genet. 10: 2775-2781, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734542</a>] [<a href="https://doi.org/10.1093/hmg/10.24.2775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11734542">Buller et al. (2001)</a> analyzed the functional importance of Eya domain missense mutations with respect to protein complex formation and cellular localization. Previously described point mutations did not alter protein localization; however, 3 mutations (glu330 to lys, <a href="#0009">601653.0009</a>; ser454 to pro, <a href="#0012">601653.0012</a>; and leu472 to arg, <a href="#0013">601653.0013</a>) disrupted interactions between Eya and the sine oculis homeobox protein (Six1; <a href="/entry/601125">601125</a>) in both yeast and mammalian cells. Binding to Six2 (<a href="/entry/604994">604994</a>) was not impeded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Rayapureddi, J. P., Kattamuri, C., Steinmetz, B. D., Frankfort, B. J., Ostrin, E. J., Mardon, G., Hegde, R. S. <strong>Eyes absent represents a class of protein tyrosine phosphatases.</strong> Nature 426: 295-298, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628052</a>] [<a href="https://doi.org/10.1038/nature02093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628052">Rayapureddi et al. (2003)</a> demonstrated that Eya is a protein-tyrosine phosphatase in Drosophila. It does not resemble the classical tyrosine phosphatases that use cysteine as a nucleophile and proceed by means of a thiol-phosphate intermediate. Rather, Eya is the prototype for a class of protein-tyrosine phosphatases that use a nucleophilic aspartic acid in a metal-dependent reaction. Furthermore, <a href="#21" class="mim-tip-reference" title="Rayapureddi, J. P., Kattamuri, C., Steinmetz, B. D., Frankfort, B. J., Ostrin, E. J., Mardon, G., Hegde, R. S. <strong>Eyes absent represents a class of protein tyrosine phosphatases.</strong> Nature 426: 295-298, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628052</a>] [<a href="https://doi.org/10.1038/nature02093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628052">Rayapureddi et al. (2003)</a> showed that the phosphatase activity of Eya contributes to its ability to induce eye formation in Drosophila. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Tootle, T. L., Silver, S. J., Davies, E. L., Newman, V., Latek, R. R., Mills, I. A., Selengut, J. D., Parlikar, B. E. W., Rebay, I. <strong>The transcription factor Eyes absent is a protein tyrosine phosphatase.</strong> Nature 426: 299-302, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628053</a>] [<a href="https://doi.org/10.1038/nature02097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628053">Tootle et al. (2003)</a> independently showed that Eya belongs to the phosphatase subgroup of the haloacid dehalogenase (HAD) superfamily, and proposed a function for it as a non-thiol-based protein-tyrosine phosphatase. Experiments performed in cultured Drosophila cells and in vitro indicated that Eya has intrinsic protein-tyrosine phosphatase activity and can autocatalytically dephosphorylate itself. Confirming the biologic significance of this function, mutations that disrupt the phosphatase active site severely compromise the ability of Eya to promote eye specification and development in Drosophila. <a href="#28" class="mim-tip-reference" title="Tootle, T. L., Silver, S. J., Davies, E. L., Newman, V., Latek, R. R., Mills, I. A., Selengut, J. D., Parlikar, B. E. W., Rebay, I. <strong>The transcription factor Eyes absent is a protein tyrosine phosphatase.</strong> Nature 426: 299-302, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628053</a>] [<a href="https://doi.org/10.1038/nature02097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628053">Tootle et al. (2003)</a> concluded that given the functional importance of phosphorylation-dependent modulation of transcription factor activity, this evidence for a nuclear transcriptional coactivator with intrinsic phosphatase activity suggests an unanticipated method of fine-tuning transcriptional regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Grifone, R., Laclef, C., Spitz, F., Lopez, S., Demignon, J., Guidotti, J.-E., Kawakami, K., Xu, P.-X., Kelly, R., Petrof, B. J., Daegelen, D., Concordet, J.-P., Maire, P. <strong>Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype.</strong> Molec. Cell. Biol. 24: 6253-6267, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15226428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15226428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15226428[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.24.14.6253-6267.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15226428">Grifone et al. (2004)</a> found that among the Six and Eya gene products expressed in mouse skeletal muscle, Six1 and Eya1 accumulated preferentially in the nuclei of fast-twitch muscles. Forced coexpression of Six1 and Eya1 in the slow-twitch soleus muscle induced a transition to a fast-twitch fiber type, with activation of fast-twitch fiber-specific genes and a switch toward glycolytic metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15226428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Alkuraya, F. S., Saadi, I., Lund, J. L., Turbe-Doan, A., Morton, C. C., Maas, R. L. <strong>SUMO1 haploinsufficiency leads to cleft lip and palate.</strong> Science 313: 1751 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990542</a>] [<a href="https://doi.org/10.1126/science.1128406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16990542">Alkuraya et al. (2006)</a> identified EYA1 as a substrate for sumoylation with SUMO1 (<a href="/entry/601912">601912</a>) in vivo. This was confirmed by abolishing the sumoylated Eya1 species with a SUMO-specific peptidase, SENP1. Furthermore, an Eya1 mutant protein in which 2 of 3 predicted high probability lysine residues were replaced with arginine displayed minimal sumoylation. In mice haploinsufficient for both Sumo1 and Eya1, the incidence of cleft lip/palate (36%) was significantly increased compared with that in mice haploinsufficient for Sumo1 (8.7%) or Eya1 (0.0%) alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16990542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Cook, P. J., Ju, B. G., Telese, F., Wang, X., Glass, C. K., Rosenfeld, M. G. <strong>Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.</strong> Nature 458: 591-596, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19234442[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/nature07849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19234442">Cook et al. (2009)</a> reported that the protein-tyrosine phosphatase EYA is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in mammalian embryonic kidney cells by executing a damage signal-dependent dephosphorylation of an H2AX (<a href="/entry/601772">601772</a>) carboxy-terminal tyrosine phosphate (Y142). This posttranslational modification determines the relative recruitment of either DNA repair or proapoptotic factors to the tail of serine-phosphorylated histone H2AX and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19234442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#1" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D. <strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong> Hum. Molec. Genet. 6: 2247-2255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361030">Abdelhak et al. (1997)</a> reported the complete genomic structure of the EYA1 gene. The gene consists of 16 coding exons and extends over 156 kb. It encodes various alternatively spliced transcripts differing only in their 5-prime regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9361030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Branchiootorenal Syndrome 1</em></strong></p><p>
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To test for possible DNA rearrangements within EYA1 in BOR probands, <a href="#2" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. <strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong> Nature Genet. 15: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>] [<a href="https://doi.org/10.1038/ng0297-157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020840">Abdelhak et al. (1997)</a> hybridized Southern blots containing DNA from 21 familial and sporadic patients with probes corresponding to exons A to G of the gene and the exon immediately adjacent to exon A (designated exon z). In a sporadic case of BOR, hybridization with exon D resulted in a signal of reduced intensity, suggesting a deletion; this reduction was not seen in the proband's parents. Hybridization with exons A and B resulted in signals of normal intensity, C resulted in a band shift, and E, F, and G resulted in bands of reduced intensity. It was estimated that the deletion in this individual spanned 5.8 to 7 kb. In another patient, <a href="#2" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. <strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong> Nature Genet. 15: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>] [<a href="https://doi.org/10.1038/ng0297-157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020840">Abdelhak et al. (1997)</a> detected a premature stop codon in exon z (<a href="#0001">601653.0001</a>); in a third patient, replacement of a T with CC insertion was detected in exon D (<a href="#0002">601653.0002</a>). The affected family members of these 2 probands carried the same mutations, whereas the unaffected family members did not. In a fourth patient, a 1-bp insertion was detected in exon c. The phenotypically normal parent of this proband did not carry this mutation. In each of 4 other individuals, a mutation was detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D. <strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong> Hum. Molec. Genet. 6: 2247-2255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361030">Abdelhak et al. (1997)</a> performed sequence analysis of the entire EYA1 coding region for 20 unrelated patients affected by BOR syndrome, and 6 novel mutations were identified. Sequence analysis of the coding region, including splice site junctions, as well as Southern blot analysis of the coding region and the 5-prime and 3-prime untranslated regions (UTRs), failed to detect anomalies in 14 of the 20 patients. Among these 14 patients, 10 represented familial cases, and, for 6 of them, linkage analysis was consistent with the involvement of EYA1. Since no evidence for genetic heterogeneity had been reported, <a href="#1" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D. <strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong> Hum. Molec. Genet. 6: 2247-2255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361030">Abdelhak et al. (1997)</a> assumed that, for these 14 patients, the mutations were located either in the promoter region, within an intron, in the 3-prime UTR, or in the most 5-prime sequences which had not yet been studied extensively. This report brought the total number of mutations detected in BOR patients to 14; all of them were different. A common feature of the mutations, however, was their location within or in the immediate vicinity of the eyaHR (also called Eya box). The region of clustering of mutations represents half of the coding sequence. Mutations outside this domain may give rise to either a lethal defect or to a discrete undetected phenotype. <a href="#1" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D. <strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong> Hum. Molec. Genet. 6: 2247-2255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361030">Abdelhak et al. (1997)</a> favored the latter hypothesis for the following reasons: 1 of the 2 patients carrying a deletion of the whole gene was exclusively affected by the BO syndrome (<a href="#11" class="mim-tip-reference" title="Haan, E. A., Hull, Y. J., White, S., Cockington, R., Charlton, P., Callen, D. F. <strong>Tricho-rhino-phalangeal and branchio-oto syndromes in a family with an inherited rearrangement of chromosome 8q.</strong> Am. J. Med. Genet. 32: 490-494, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2773990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2773990</a>] [<a href="https://doi.org/10.1002/ajmg.1320320412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2773990">Haan et al., 1989</a>), and the only mutation that had been detected outside the eyaHR was also present in a BOR-affected patient (<a href="#0004">601653.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2773990+9361030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Kumar, S., Kimberling, W. J., Weston, M. D., Schaefer, B. G., Berg, M. A., Marres, H. A. M., Cremers, C. W. R. J. <strong>Identification of three novel mutations in human EYA1 protein associated with branchio-oto-renal syndrome.</strong> Hum. Mutat. 11: 443-449, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9603436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9603436</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:6<443::AID-HUMU4>3.0.CO;2-S" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9603436">Kumar et al. (1998)</a> identified 3 novel mutations in the EYA1 gene in patients with the BOR syndrome, 1 of which was a 4-bp deletion in a family originally reported by <a href="#24" class="mim-tip-reference" title="Rowley, P. T. <strong>Familial hearing loss associated with branchial fistulas.</strong> Pediatrics 44: 978-985, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5365063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5365063</a>]" pmid="5365063">Rowley (1969)</a>. <a href="#15" class="mim-tip-reference" title="Kumar, S., Deffenbacher, K., Cremers, C. W. R. J., Van Camp, G., Kimberling, W. J. <strong>Branchio-oto-renal syndrome: identification of novel mutations, molecular characterization, mutation distribution, and prospects for genetic testing.</strong> Genet. Test. 1: 243-251, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10464653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10464653</a>] [<a href="https://doi.org/10.1089/gte.1997.1.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10464653">Kumar et al. (1998)</a> found reports of 20 mutations in the EYA1 gene, most of them clustered in the C-terminal region (exons 9 to 16), in cases of BOR syndrome. <a href="#22" class="mim-tip-reference" title="Rickard, S., Boxer, M., Trompeter, R., Bitner-Glindzicz, M. <strong>Importance of clinical evaluation and molecular testing in the branchio-oto-renal (BOR) syndrome and overlapping phenotypes. (Letter)</strong> J. Med. Genet. 37: 623-627, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10991693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10991693</a>] [<a href="https://doi.org/10.1136/jmg.37.8.623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10991693">Rickard et al. (2000)</a> identified mutations in 11 of 18 individuals with classic BOR. They found no mutations in individuals with atypical BOR syndrome or OTFC syndrome. The mutations identified were clustered in exons 9 to 16 with 3 in exon 8 and 1 in exon 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9603436+10464653+10991693+5365063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Vervoort, V. S., Smith, R. J. H., O'Brien, J., Schroer, R., Abbott, A., Stevenson, R. E., Schwartz, C. E. <strong>Genomic rearrangements of EYA1 account for a large fraction of families with BOR syndrome.</strong> Europ. J. Hum. Genet. 10: 757-766, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404110</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12404110">Vervoort et al. (2002)</a> noted that in up to one-half of reported cases of BOR syndrome, EYA1 screening was negative, suggesting genetic heterogeneity. Using SSCP and direct sequencing, they screened the coding region of the EYA1 gene in a panel of BOR families linked to chromosome 8. Only 1 point mutation in 5 probands was detected. However, using Southern blot analysis, complex rearrangements such as inversions and large deletions were identified in the other 4 patients. <a href="#29" class="mim-tip-reference" title="Vervoort, V. S., Smith, R. J. H., O'Brien, J., Schroer, R., Abbott, A., Stevenson, R. E., Schwartz, C. E. <strong>Genomic rearrangements of EYA1 account for a large fraction of families with BOR syndrome.</strong> Europ. J. Hum. Genet. 10: 757-766, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404110</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12404110">Vervoort et al. (2002)</a> concluded that more complex rearrangements may have been missed in earlier studies, which commonly used only SSCP and sequencing for mutation detection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12404110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Chang, E. H., Menezes, M., Meyer, N. C., Cucci, R. A., Vervoort, V. S., Schwartz, C. E., Smith, R. J. H. <strong>Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences.</strong> Hum. Mutat. 23: 582-589, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15146463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15146463</a>] [<a href="https://doi.org/10.1002/humu.20048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15146463">Chang et al. (2004)</a> sought to refine the clinical diagnosis of BOR syndrome by analyzing phenotypic data from families segregating EYA1 disease-causing mutations. Based on genotype-phenotype analyses, they proposed new criteria for the clinical diagnosis of BOR syndrome. The authors found that in approximately 40% of patients meeting their criteria, EYA1 mutations were identified. Of these mutations, 80% were coding sequence variants identified by SSCP, and 20% were complex genomic rearrangements identified by a semiquantitative PCR-based screen. <a href="#6" class="mim-tip-reference" title="Chang, E. H., Menezes, M., Meyer, N. C., Cucci, R. A., Vervoort, V. S., Schwartz, C. E., Smith, R. J. H. <strong>Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences.</strong> Hum. Mutat. 23: 582-589, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15146463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15146463</a>] [<a href="https://doi.org/10.1002/humu.20048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15146463">Chang et al. (2004)</a> concluded that genetic testing of EYA1 should include analysis of the coding sequence and a screen for complex rearrangements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15146463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Migliosi, V., Flex, E., Guida, V., Martini, A., Giarbini, N., Markova, T., Torrente, I., Dallapiccola, B. <strong>Identification of five novel BOR mutations in human EYA1 gene associated with branchio-oto-renal syndrome by a DHPLC-based assay. (Letter)</strong> Clin. Genet. 66: 478-480, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15479196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15479196</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00318.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15479196">Migliosi et al. (2004)</a> used an analysis based on denaturing high performance liquid chromatography (DHPLC) to identify 5 novel mutations in the EYA1 gene associated with BOR syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15479196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Orten, D. J., Fischer, S. M., Sorensen, J. L., Radhakrishna, U., Cremers, C. W. R. J., Marres, H. A. M., Van Camp, G., Welch, K. O., Smith, R. J. H., Kimberling, W. J. <strong>Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR.</strong> Hum. Mutat. 29: 537-544, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18220287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18220287</a>] [<a href="https://doi.org/10.1002/humu.20691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18220287">Orten et al. (2008)</a> identified 70 different EYA1 mutations in 89 of 435 families with BOR or a related phenotype. EYA1 mutations were found in 76 (31%) of 248 families fitting established clinical criteria for BOR and 13 (7%) of 187 families with a questionable BOR phenotype. Most of the mutations were private, and there were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18220287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Stockley, T. L., Mendoza-Londono, R., Propst, E. J., Sodhi, S., Dupuis, L., Papsin, B. C. <strong>A recurrent EYA1 mutation causing alternative RNA splicing in branchio-oto-renal syndrome: implications for molecular diagnostics and disease mechanism.</strong> Am. J. Med. Genet. 149A: 322-327, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206155</a>] [<a href="https://doi.org/10.1002/ajmg.a.32679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206155">Stockley et al. (2009)</a> identified EYA1 mutations (see, e.g., <a href="#0016">601653.0016</a>) in 14 (82%) of 17 unrelated probands with BOR syndrome. De novo mutations were confirmed in 45% of the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient carrying a mutation in the SIX5 gene (T552M; <a href="/entry/600963#0004">600963.0004</a>), <a href="#14" class="mim-tip-reference" title="Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L. <strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong> Hum. Mutat. 32: 183-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21280147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21280147</a>] [<a href="https://doi.org/10.1002/humu.21402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21280147">Krug et al. (2011)</a> identified a mutation in the EYA1 gene, a deletion removing exons 3, 4, and 5. This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This observation, in addition to the extreme rarity of SIX5 mutations, caused <a href="#14" class="mim-tip-reference" title="Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L. <strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong> Hum. Mutat. 32: 183-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21280147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21280147</a>] [<a href="https://doi.org/10.1002/humu.21402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21280147">Krug et al. (2011)</a> to reconsider the role of SIX5 in branchiootorenal syndrome etiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21280147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Branchiootic Syndrome 1</em></strong></p><p>
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To address the question of whether the branchiootic syndrome (BOS1; <a href="/entry/602588">602588</a>) is the same as branchiootorenal dysplasia, <a href="#30" class="mim-tip-reference" title="Vincent, C., Kalatzis, V., Abdelhak, S., Chaib, H., Compain, S., Helia, J., Vaneecloo, F.-M., Petit, C. <strong>BOR and BO syndromes are allelic defects of EYA1.</strong> Europ. J. Hum. Genet. 5: 242-246, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9359046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9359046</a>]" pmid="9359046">Vincent et al. (1997)</a> studied 2 large kindreds in each of which 8 affected members presented exclusively with BO syndrome (without the association of renal anomalies). In both kindreds, linkage analysis mapped the causative gene to the same chromosomal region as the EYA1 gene. A search for mutations in 9 of the EYA1 coding exons identified a 2-bp insertion (<a href="#0003">601653.0003</a>) segregating in 1 family, and an 8-bp deletion (<a href="/entry/601053#0004">601053.0004</a>) segregating in the other. Thus, the BOR and BO syndromes are allelic defects in the EYA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9359046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Anterior Segment Anomalies</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Azuma, N., Hirakiyama, A., Inoue, T., Asaka, A., Yamada, M. <strong>Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.</strong> Hum. Molec. Genet. 9: 363-366, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655545</a>] [<a href="https://doi.org/10.1093/hmg/9.3.363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655545">Azuma et al. (2000)</a> examined genomic DNA isolated from patients with various types of developmental eye anomalies for EYA1 mutations by the use of PCR-SSCP and sequencing. They identified 3 novel missense mutations in patients who had congenital cataracts and ocular anterior segment anomalies (see <a href="#0008">601653.0008</a>-<a href="#0010">601653.0010</a>). One of the patients had clinical features of BOR syndrome as well (see <a href="#0010">601653.0010</a>). These results implied that the human EYA1 gene is also involved in eye morphogenesis, and that a wide variety of clinical manifestations may be caused by EYA mutations. Mutations were heterozygous in all 3 probands; 2 of the 3 were sporadic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Otofaciocervical Syndrome</em></strong></p><p>
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<a href="#23" class="mim-tip-reference" title="Rickard, S., Parker, M., van't Hoff, W., Barnicoat, A., Russell-Eggitt, I., Winter, R. M., Bitner-Glindzicz, M. <strong>Oto-facial-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1: molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM.</strong> Hum. Genet. 108: 398-403, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409867</a>] [<a href="https://doi.org/10.1007/s004390100495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11409867">Rickard et al. (2001)</a> presented evidence that the otofaciocervical syndrome (OTFCS1; <a href="/entry/166780">166780</a>) is a contiguous gene deletion syndrome involving the EYA1 gene, which is the site of mutations causing the branchiootorenal syndrome. They speculated that the differences between the 2 syndromes might be related to undefined genes included in the deleted region accounting for additional traits seen in OTFCS. <a href="#8" class="mim-tip-reference" title="Estefania, E., Ramirez-Camacho, R., Gomar, M., Trinidad, A., Arellano, B., Garcia-Berrocal, J. R., Verdaguer, J. M., Vilches, C. <strong>Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome.</strong> Ann. Hum. Genet. 70: 140-144, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16441263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16441263</a>] [<a href="https://doi.org/10.1111/j.1529-8817.2005.00204.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16441263">Estefania et al. (2006)</a> reported a patient with a splice site mutation in the EYA1 gene (<a href="#0014">601653.0014</a>) and clinical changes thought to be characteristic of OTFCS, namely, alterations of the face and shoulder girdle in addition to malformations seen in BOR. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11409867+16441263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#13" class="mim-tip-reference" title="Johnson, K. R., Cook, S. A., Erway, L. C., Matthews, A. N., Sanford, L. P., Paradies, N. E., Friedman, R. A. <strong>Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome.</strong> Hum. Molec. Genet. 8: 645-653, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072433</a>] [<a href="https://doi.org/10.1093/hmg/8.4.645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072433">Johnson et al. (1999)</a> described a spontaneous mutation causing deafness and circling behavior in a C3H/HeJ colony of mice. Pathologic analysis of mutant mice showed gross morphologic abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior were shown to be inherited as an autosomal recessive trait, and were mapped to chromosome 1, near the position of the Eya1 gene (<a href="#33" class="mim-tip-reference" title="Xu, P.-X., Woo, I., Her, H., Beier, D. R., Maas, R. L. <strong>Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode.</strong> Development 124: 219-231, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9006082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9006082</a>] [<a href="https://doi.org/10.1242/dev.124.1.219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9006082">Xu et al., 1997</a>). Molecular analysis of the Eya1 gene in mutant mice revealed insertion of an intracisternal A particle (IAP) element in intron 7. The presence of the IAP insertion was associated with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. <a href="#13" class="mim-tip-reference" title="Johnson, K. R., Cook, S. A., Erway, L. C., Matthews, A. N., Sanford, L. P., Paradies, N. E., Friedman, R. A. <strong>Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome.</strong> Hum. Molec. Genet. 8: 645-653, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072433</a>] [<a href="https://doi.org/10.1093/hmg/8.4.645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072433">Johnson et al. (1999)</a> designated the new mouse mutation Eya1(bor) to denote that it appears to be an authentic model of the human BOR syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10072433+9006082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, <a href="#9" class="mim-tip-reference" title="Floyd, J. A., Gold, D. A., Concepcion, D., Poon, T. H., Wang, X., Keithley, E., Chen, D., Ward, E. J., Chinn, S. B., Friedman, R. A., Yu, H.-T., Moriwaki, K., Shiroishi, T., Hamilton, B. A. <strong>A natural allele of Nxf1 suppresses retrovirus insertional mutations.</strong> Nature Genet. 35: 221-228, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14517553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14517553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14517553[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/ng1247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14517553">Floyd et al. (2003)</a> studied the modifier-of-vibrator-1 locus (Mvb1), which controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, such as occurs in the Eya1(BOR) model of human branchiootorenal syndrome. By positional complementation cloning, they identified Mvb1 as the nuclear export factor Nxf1 (<a href="/entry/602647">602647</a>), providing an unexpected link between the mRNA export receptor and pre-mRNA processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14517553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 understand the developmental pathogenesis of organs affected in BOR syndrome and BO syndrome, <a href="#31" class="mim-tip-reference" title="Xu, P.-X., Adams, J., Peters, H., Brown, M. C., Heaney, S., Maas, R. <strong>Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia.</strong> Nature Genet. 23: 113-117, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471511</a>] [<a href="https://doi.org/10.1038/12722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471511">Xu et al. (1999)</a> inactivated the Eya1 gene in mice. Eya1 heterozygotes showed renal abnormalities and a conductive hearing loss similar to BOR syndrome, whereas Eya1 homozygotes lacked ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia. Inner ear development in Eya1 homozygotes arrested at the otic vesicle stage, and all components of the inner ear and specific cranial sensory ganglia failed to form. In the kidney, Eya1 homozygosity resulted in an absence of ureteric bud outgrowth and a subsequent failure of metanephric induction. Gdnf (<a href="/entry/600837">600837</a>) expression, which is required to direct ureteric bud outgrowth via activation of the RET receptor tyrosine kinase (<a href="/entry/164761">164761</a>), was not detected in Eya1 -/- metanephric mesenchyme. In Eya1 -/- ear and kidney development, Six (see SIX1; <a href="/entry/601205">601205</a>) but not Pax (see PAX2; <a href="/entry/167409">167409</a>) expression was Eya1 dependent, similar to a genetic pathway elucidated in the Drosophila eye imaginal disc. The results indicated that EYA1 controls critical early inductive signaling events involved in ear and kidney formation, and integrated EYA1 into the genetic regulatory cascade controlling kidney formation upstream of GDNF. In addition, the results suggested that an evolutionarily conserved PAX-EYA-SIX regulatory hierarchy is used in mammalian ear and kidney development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G. <strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong> Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628042</a>] [<a href="https://doi.org/10.1038/nature02083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628042">Li et al. (2003)</a> reported that Six1 is required for the development of murine kidney, muscle, and inner ear and that it exhibits synergistic genetic interactions with Eya factors. <a href="#17" class="mim-tip-reference" title="Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G. <strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong> Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628042</a>] [<a href="https://doi.org/10.1038/nature02083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628042">Li et al. (2003)</a> demonstrated that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach (<a href="/entry/603803">603803</a>) from repression to activation, causing transcriptional activation through recruitment of coactivators. The gene-specific recruitment of a coactivator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis. Eya1 +/- Six1 +/- double heterozygous mice had a defect in kidney development, which was not observed in single heterozygotes for either gene deletion, suggesting that Six1 and Eya1 act in the same genetic pathway. Notably, there was a complete absence of all hypaxial muscle in Six1 -/- Eya1 -/- double knockout mice and severe reduction of epaxial muscle, a phenotype resembling that seen in mice homozygous for deletion of Myog (<a href="/entry/159980">159980</a>) and in double knockouts for MyoD (<a href="/entry/159970">159970</a>)/Myf5 (<a href="/entry/159990">159990</a>) and Pax3 (<a href="/entry/606597">606597</a>)/Myf5. Interestingly, although mutation of Six1 or Eya1 has minimal or no effect on pituitary development, mice with both genes deleted have a pituitary that is approximately 5- to 10-fold smaller by volume than the wildtype gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>17 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601653[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909195 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909195;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/rs121909195?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=rs121909195" 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=rs121909195" 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=RCV000008391 OR RCV000844696 OR RCV001851734 OR RCV002259304 OR RCV003390657 OR RCV005049321" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008391, RCV000844696, RCV001851734, RCV002259304, RCV003390657, RCV005049321" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008391...</a>
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<p>In a familial case of BOR syndrome (BOR1; <a href="/entry/113650">113650</a>), <a href="#2" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. <strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong> Nature Genet. 15: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>] [<a href="https://doi.org/10.1038/ng0297-157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020840">Abdelhak et al. (1997)</a> demonstrated a C-to-T transition of nucleotide 823 in exon z, resulting in a change of codon 275 from arginine to stop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a familial case of BOR syndrome (BOR1; <a href="/entry/113650">113650</a>), <a href="#2" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. <strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong> Nature Genet. 15: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>] [<a href="https://doi.org/10.1038/ng0297-157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020840">Abdelhak et al. (1997)</a> demonstrated substitution of 1251T with CC in exon D, resulting in a frameshift and premature termination of transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a kindred in which 8 members in 3 generations had the branchiootic syndrome (BOS1; <a href="/entry/602588">602588</a>) (without renal anomalies), <a href="#30" class="mim-tip-reference" title="Vincent, C., Kalatzis, V., Abdelhak, S., Chaib, H., Compain, S., Helia, J., Vaneecloo, F.-M., Petit, C. <strong>BOR and BO syndromes are allelic defects of EYA1.</strong> Europ. J. Hum. Genet. 5: 242-246, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9359046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9359046</a>]" pmid="9359046">Vincent et al. (1997)</a> demonstrated linkage to the same region of chromosome 8 where the EYA1 gene is located. Furthermore, they demonstrated a 2-bp (GT) insertion in exon A, at position 870. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9359046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a family with 8 living members in 3 generations showing BO syndrome (BOS1; <a href="/entry/602588">602588</a>), <a href="#30" class="mim-tip-reference" title="Vincent, C., Kalatzis, V., Abdelhak, S., Chaib, H., Compain, S., Helia, J., Vaneecloo, F.-M., Petit, C. <strong>BOR and BO syndromes are allelic defects of EYA1.</strong> Europ. J. Hum. Genet. 5: 242-246, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9359046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9359046</a>]" pmid="9359046">Vincent et al. (1997)</a> demonstrated an 8-bp deletion at position 297 (297del8) of the EYA1 gene. The mutation resulted in a frameshift leading to a premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9359046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008395" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008395" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008395</a>
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<p>In a mother and daughter with BOR syndrome (BOR1; <a href="/entry/113650">113650</a>), <a href="#1" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D. <strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong> Hum. Molec. Genet. 6: 2247-2255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361030">Abdelhak et al. (1997)</a> demonstrated that the EYA1 gene carried an inserted Alu element in exon 10. The inserted element was in opposite orientation to that of the gene itself, and the 3-prime sequence of the Alu element was followed by a long poly(A) tail. The features were entirely consistent with retrotransposition. A difference in length of the poly(A) tail, which was reduced from poly(A)97 to poly(A)31 when transmitted from mother to daughter, demonstrated instability. The transposition was a de novo insertion as it was not present in the DNA from the maternal grandparents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9361030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 BRANCHIOOTORENAL SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231355 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231355;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=rs606231355" 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=rs606231355" 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=RCV000008396" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008396" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008396</a>
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<p>In a family reported originally by <a href="#24" class="mim-tip-reference" title="Rowley, P. T. <strong>Familial hearing loss associated with branchial fistulas.</strong> Pediatrics 44: 978-985, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5365063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5365063</a>]" pmid="5365063">Rowley (1969)</a>, <a href="#16" class="mim-tip-reference" title="Kumar, S., Kimberling, W. J., Weston, M. D., Schaefer, B. G., Berg, M. A., Marres, H. A. M., Cremers, C. W. R. J. <strong>Identification of three novel mutations in human EYA1 protein associated with branchio-oto-renal syndrome.</strong> Hum. Mutat. 11: 443-449, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9603436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9603436</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:6<443::AID-HUMU4>3.0.CO;2-S" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9603436">Kumar et al. (1998)</a> demonstrated association of the BOR syndrome (BOR1; <a href="/entry/113650">113650</a>) with a 4-bp deletion at nucleotide 1501 of the EYA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9603436+5365063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0007 BRANCHIOOTORENAL SYNDROME 1</strong>
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EYA1, ARG407GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909196;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=rs121909196" 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=rs121909196" 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=RCV000008397 OR RCV000844628 OR RCV001849260 OR RCV002228019 OR RCV002288475 OR RCV004739295 OR RCV004795383" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008397, RCV000844628, RCV001849260, RCV002228019, RCV002288475, RCV004739295, RCV004795383" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008397...</a>
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<p>In a case of familial BOR syndrome (BOR1; <a href="/entry/113650">113650</a>), <a href="#15" class="mim-tip-reference" title="Kumar, S., Deffenbacher, K., Cremers, C. W. R. J., Van Camp, G., Kimberling, W. J. <strong>Branchio-oto-renal syndrome: identification of novel mutations, molecular characterization, mutation distribution, and prospects for genetic testing.</strong> Genet. Test. 1: 243-251, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10464653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10464653</a>] [<a href="https://doi.org/10.1089/gte.1997.1.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10464653">Kumar et al. (1998)</a> identified a G-to-A transition at nucleotide 1220 in exon 12, resulting in an arg407-to-gln substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10464653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ANTERIOR SEGMENT ANOMALIES AND CATARACT</strong>
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EYA1, ARG514GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909197 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909197;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=rs121909197" 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=rs121909197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008398" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008398" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008398</a>
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<p>In a 4-year-old Japanese girl with congenital cataracts and ocular anterior segment anomalies (see BOS1, <a href="/entry/602588">602588</a>), <a href="#4" class="mim-tip-reference" title="Azuma, N., Hirakiyama, A., Inoue, T., Asaka, A., Yamada, M. <strong>Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.</strong> Hum. Molec. Genet. 9: 363-366, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655545</a>] [<a href="https://doi.org/10.1093/hmg/9.3.363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655545">Azuma et al. (2000)</a> found an A-to-G transition at position 1688 of the cDNA corresponding to the EYA1 gene, expected to result in an arg514-to-gly amino acid substitution. Ocular examinations revealed central corneal opacity, adhesion to the iris (Peters anomaly), and slight cataracts in both eyes, whereas the fundus was normal. Her mother, aged 32, had nuclear-type congenital cataracts. The patient and her mother were otherwise normal in appearance, intelligence, and karyotype. No clinical findings suggesting BO/BOR syndrome were detected except for a slight elevation of the auditory brainstem response (ABR) threshold in hearing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<strong>.0009 ANTERIOR SEGMENT ANOMALIES</strong>
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EYA1, GLU330LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909198 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909198;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=rs121909198" 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=rs121909198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008399" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008399" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008399</a>
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<p>In a 3-year-old Japanese boy with an iris anomaly (see BOS1, <a href="/entry/602588">602588</a>), <a href="#4" class="mim-tip-reference" title="Azuma, N., Hirakiyama, A., Inoue, T., Asaka, A., Yamada, M. <strong>Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.</strong> Hum. Molec. Genet. 9: 363-366, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655545</a>] [<a href="https://doi.org/10.1093/hmg/9.3.363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655545">Azuma et al. (2000)</a> found a glu330-to-lys mutation due to a G-to-A transition at position 1136 (exon 10) of the EYA1 gene. The mutation was not detected in his parents, who were apparently normal. Examinations revealed bilateral persistence of the pupillary membrane, but a normal lens and fundus. He had no other systemic abnormalities and was found to be normal in growth and intelligence for his age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 BRANCHIOOTORENAL SYNDROME WITH CATARACT</strong>
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EYA1, GLY393SER
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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> rs121909199 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909199;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/rs121909199?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=rs121909199" 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=rs121909199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008400 OR RCV000309264 OR RCV000367199 OR RCV000496093 OR RCV000606853 OR RCV000657911 OR RCV004619188 OR RCV005089208" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008400, RCV000309264, RCV000367199, RCV000496093, RCV000606853, RCV000657911, RCV004619188, RCV005089208" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008400...</a>
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<p><a href="#4" class="mim-tip-reference" title="Azuma, N., Hirakiyama, A., Inoue, T., Asaka, A., Yamada, M. <strong>Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.</strong> Hum. Molec. Genet. 9: 363-366, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655545</a>] [<a href="https://doi.org/10.1093/hmg/9.3.363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655545">Azuma et al. (2000)</a> identified a gly393-to-ser mutation in an 8-year-old boy who first presented at their hospital with nystagmus and systemic edema at 20 days of age. Examinations revealed bilateral nuclear-type congenital cataracts with a normal fundus, and multicystic dysplasia in his right kidney, which did not function and caused hypocalcemia. The cataracts were operated on at 1 month of age and the right kidney was removed at 2 months. He was later found to have conductive deafness with the malleus anomaly. He also had cervical fistula that occluded spontaneously. Except for the cataracts, the clinical findings were considered typical of BOR syndrome (BOR1; <a href="/entry/113650">113650</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0011 BRANCHIOOTORENAL SYNDROME 1</strong>
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EYA1, 1-BP INS, 387T
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008401</a>
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<p>In a patient with classic BOR syndrome (BOR1; <a href="/entry/113650">113650</a>) with a single kidney, <a href="#22" class="mim-tip-reference" title="Rickard, S., Boxer, M., Trompeter, R., Bitner-Glindzicz, M. <strong>Importance of clinical evaluation and molecular testing in the branchio-oto-renal (BOR) syndrome and overlapping phenotypes. (Letter)</strong> J. Med. Genet. 37: 623-627, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10991693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10991693</a>] [<a href="https://doi.org/10.1136/jmg.37.8.623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10991693">Rickard et al. (2000)</a> identified a 1-bp insertion at nucleotide 387 in exon 5 of the EYA1 gene. The authors concluded that mutations located outside exons 9 to 16 do not appear to result in different renal manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10991693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121909200 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909200;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/rs121909200?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=rs121909200" 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=rs121909200" 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=RCV000008402 OR RCV003593858 OR RCV004739296" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008402, RCV003593858, RCV004739296" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008402...</a>
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<p>In a family with BOR syndrome (BOR1; <a href="/entry/113650">113650</a>), <a href="#1" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D. <strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong> Hum. Molec. Genet. 6: 2247-2255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361030">Abdelhak et al. (1997)</a> identified a ser454-to-pro (S454P) mutation in exon 13 of the EYA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9361030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121909201 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909201;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=rs121909201" 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=rs121909201" 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=RCV000008403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008403</a>
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<p>In a family with BOR syndrome (BOR1; <a href="/entry/113650">113650</a>), <a href="#1" class="mim-tip-reference" title="Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D. <strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong> Hum. Molec. Genet. 6: 2247-2255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361030">Abdelhak et al. (1997)</a> identified a leu472-to-arg (L472R) mutation in exon 14 of the EYA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9361030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0014 OTOFACIOCERVICAL SYNDROME 1 (1 patient)</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">rs869025180 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025180;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=rs869025180" 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=rs869025180" 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=RCV000008404 OR RCV002512904" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008404, RCV002512904" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008404...</a>
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<p>In a patient thought to have otofaciocervical syndrome (OFC1; <a href="/entry/166780">166780</a>), <a href="#8" class="mim-tip-reference" title="Estefania, E., Ramirez-Camacho, R., Gomar, M., Trinidad, A., Arellano, B., Garcia-Berrocal, J. R., Verdaguer, J. M., Vilches, C. <strong>Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome.</strong> Ann. Hum. Genet. 70: 140-144, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16441263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16441263</a>] [<a href="https://doi.org/10.1111/j.1529-8817.2005.00204.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16441263">Estefania et al. (2006)</a> found a de novo heterozygous nucleotide substitution at the beginning of intron 6 of the EYA1 gene (540+1G-A). The patient had bilateral conductive hearing loss, a long and narrow face, preauricular and cervical pits, prominent and cupped ears, a high-arched palate, sloping shoulders and clavicles, and trapezius hypoplasia which allowed adduction of the shoulders. Chest x-ray showed diastasis of the right sternoclavicular joint, and urography demonstrated bilateral sponge kidneys. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16441263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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EYA1, ARG328TER
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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> rs121909202 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909202;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/rs121909202?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=rs121909202" 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=rs121909202" 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=RCV000008405 OR RCV000008406 OR RCV001823094 OR RCV002228020 OR RCV002512905 OR RCV004554585 OR RCV005042015" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008405, RCV000008406, RCV001823094, RCV002228020, RCV002512905, RCV004554585, RCV005042015" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008405...</a>
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<p>In an infant with a variant form of branchiootic syndrome (BOS1; <a href="/entry/602588">602588</a>), <a href="#26" class="mim-tip-reference" title="Spruijt, L., Hoefsloot, L. H., van Schaijk, G. H. W. H., van Waardenburg, D., Kremer, B., Brackel, H. J. L., de Die-Smulders, C. E. M. <strong>Identification of a novel EYA1 mutation presenting in a newborn with laryngomalacia, glossoptosis, retrognathia, and pectus excavatum. (Letter)</strong> Am. J. Med. Genet. 140A: 1343-1345, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16691597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16691597</a>] [<a href="https://doi.org/10.1002/ajmg.a.31285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16691597">Spruijt et al. (2006)</a> identified a heterozygous 982C-T transition in exon 10 of the EYA1 gene, resulting in an arg328-to-ter (R328X) substitution predicted to lead to a nonfunctional protein. The patient had severe obstructive sleep apnea caused by laryngomalacia, pharyngomalacia, glossoptosis, and tracheobronchomalacia. He also had retrognathia, bilateral branchial fistulae, ear anomalies, including ear pits, simple helices, and slight cup-shaped and low-set left ear. His mother, who also carried the mutation, had mild retrognathia, left-sided branchial neck fistula, left-sided preauricular pit, and right-sided branchial cyst in the neck. Kidney ultrasound and hearing were normal in both the mother and son. The findings expanded the phenotypic anomalies of BO syndrome associated with EYA1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16691597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Olavarrieta, L., Morales-Angulo, C., del Castillo, I., Moreno, F., Moreno-Pelayo, M. A. <strong>Stickler and branchio-oto-renal syndromes in a patient with mutations in EYA1 and COL2A1 genes.</strong> Clin. Genet. 73: 262-267, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18177466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18177466</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00947.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18177466">Olavarrieta et al. (2008)</a> identified a de novo R328X mutation in the EYA1 gene in a Spanish man with branchiootorenal syndrome (BOR1; <a href="/entry/113650">113650</a>). He had branchial fistulae, preauricular pits, renal agenesis, and mixed hearing loss. In addition, he had myopia, vitreous anomaly, flat face, and cleft palate, characteristic of Stickler syndrome type I (STL1; <a href="/entry/108300">108300</a>) and was found to also carry a mutation in the COL2A1 gene (<a href="/entry/120140">120140</a>). <a href="#19" class="mim-tip-reference" title="Olavarrieta, L., Morales-Angulo, C., del Castillo, I., Moreno, F., Moreno-Pelayo, M. A. <strong>Stickler and branchio-oto-renal syndromes in a patient with mutations in EYA1 and COL2A1 genes.</strong> Clin. Genet. 73: 262-267, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18177466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18177466</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00947.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18177466">Olavarrieta et al. (2008)</a> emphasized that both disorders show phenotypic variability as well as overlapping features, which can complicate a precise diagnosis. Thorough clinical evaluation is necessary to identify coexisting genetic syndromes in the same patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18177466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs606231356 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231356;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=rs606231356" 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=rs606231356" 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 Japanese girl with features of the branchiootic syndrome (BOS1; <a href="/entry/602588">602588</a>), <a href="#25" class="mim-tip-reference" title="Shimasaki, N., Watanabe, K., Hara, M., Kosaki, K. <strong>EYA1 mutation in a newborn female presenting with cardiofacial syndrome.</strong> Pediat. Cardiol. 25: 411-413, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15493068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15493068</a>] [<a href="https://doi.org/10.1007/s00246-003-0271-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15493068">Shimasaki et al. (2004)</a> identified a heterozygous 7-bp deletion (1402delACAACTA) in exon 14 of the EYA1 gene, resulting in a frameshift and premature termination of the protein at codon 483. The child had preauricular pits, cupped ears, hearing loss, and bilateral cysts over the sternocleid muscle. The mutation was most likely transmitted by the mother, who also had features of the branchiootic syndrome, although this was not confirmed by molecular testing. The patient also had features consistent with the Cayler cardiofacial syndrome (<a href="/entry/125520">125520</a>), including asymmetric facies while crying and a large patent ductus arteriosus. <a href="#25" class="mim-tip-reference" title="Shimasaki, N., Watanabe, K., Hara, M., Kosaki, K. <strong>EYA1 mutation in a newborn female presenting with cardiofacial syndrome.</strong> Pediat. Cardiol. 25: 411-413, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15493068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15493068</a>] [<a href="https://doi.org/10.1007/s00246-003-0271-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15493068">Shimasaki et al. (2004)</a> suggested that the BO syndrome and Cayler syndrome may represent a spectrum of diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15493068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs606231357 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231357;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=rs606231357" 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=rs606231357" 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=RCV000008408 OR RCV001569391 OR RCV001851735" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008408, RCV001569391, RCV001851735" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008408...</a>
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<p>In affected members of 3 of 17 unrelated families with BOR syndrome (BOR1; <a href="/entry/113650">113650</a>), <a href="#27" class="mim-tip-reference" title="Stockley, T. L., Mendoza-Londono, R., Propst, E. J., Sodhi, S., Dupuis, L., Papsin, B. C. <strong>A recurrent EYA1 mutation causing alternative RNA splicing in branchio-oto-renal syndrome: implications for molecular diagnostics and disease mechanism.</strong> Am. J. Med. Genet. 149A: 322-327, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206155</a>] [<a href="https://doi.org/10.1002/ajmg.a.32679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206155">Stockley et al. (2009)</a> identified a heterozygous G-to-A transition in intron 8 of the EYA1 gene (867+5G-A), resulting in a transcript lacking exon 8, predicting a frameshift and premature termination within exon 9. The mutation was not found in 100 control chromosomes. The same mutation was also found in 2 additional unrelated BOR probands outside of the original cohort. Haplotype analysis did not indicate a founder effect. RT-PCR analysis showed that the transcript produced by the splice site mutation escaped nonsense-mediated mRNA decay and produced a truncated protein containing only the N-terminal coactivator region, but not the C-terminal phosphatase domain. <a href="#27" class="mim-tip-reference" title="Stockley, T. L., Mendoza-Londono, R., Propst, E. J., Sodhi, S., Dupuis, L., Papsin, B. C. <strong>A recurrent EYA1 mutation causing alternative RNA splicing in branchio-oto-renal syndrome: implications for molecular diagnostics and disease mechanism.</strong> Am. J. Med. Genet. 149A: 322-327, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206155</a>] [<a href="https://doi.org/10.1002/ajmg.a.32679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206155">Stockley et al. (2009)</a> suggested that this resulted in a combination of dominant-negative gain of function and haploinsufficiency. The renal phenotype was severe in affected individuals, including renal agenesis, structural abnormalities, and renal artery dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D.
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<strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong>
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Hum. Molec. Genet. 6: 2247-2255, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9361030" 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/6.13.2247" target="_blank">Full Text</a>]
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Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C.
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<strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong>
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Nature Genet. 15: 157-164, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020840</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020840" 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/ng0297-157" target="_blank">Full Text</a>]
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Alkuraya, F. S., Saadi, I., Lund, J. L., Turbe-Doan, A., Morton, C. C., Maas, R. L.
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<strong>SUMO1 haploinsufficiency leads to cleft lip and palate.</strong>
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Science 313: 1751 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16990542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1128406" target="_blank">Full Text</a>]
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Azuma, N., Hirakiyama, A., Inoue, T., Asaka, A., Yamada, M.
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<strong>Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.</strong>
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Hum. Molec. Genet. 9: 363-366, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655545</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Buller, C., Xu, X., Marquis, V., Schwanke, R., Xu, P.-X.
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<strong>Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.</strong>
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Hum. Molec. Genet. 10: 2775-2781, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chang, E. H., Menezes, M., Meyer, N. C., Cucci, R. A., Vervoort, V. S., Schwartz, C. E., Smith, R. J. H.
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<strong>Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10991693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10991693</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10991693" 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/10.1136/jmg.37.8.623" target="_blank">Full Text</a>]
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<a id="Rickard2001" class="mim-anchor"></a>
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Rickard, S., Parker, M., van't Hoff, W., Barnicoat, A., Russell-Eggitt, I., Winter, R. M., Bitner-Glindzicz, M.
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<strong>Oto-facial-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1: molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM.</strong>
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Hum. Genet. 108: 398-403, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11409867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390100495" target="_blank">Full Text</a>]
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<a id="Rowley1969" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rowley, P. T.
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<strong>Familial hearing loss associated with branchial fistulas.</strong>
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Pediatrics 44: 978-985, 1969.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5365063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5365063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5365063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Shimasaki2004" class="mim-anchor"></a>
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Shimasaki, N., Watanabe, K., Hara, M., Kosaki, K.
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<strong>EYA1 mutation in a newborn female presenting with cardiofacial syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15493068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15493068</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15493068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00246-003-0271-3" target="_blank">Full Text</a>]
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Spruijt, L., Hoefsloot, L. H., van Schaijk, G. H. W. H., van Waardenburg, D., Kremer, B., Brackel, H. J. L., de Die-Smulders, C. E. M.
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<strong>Identification of a novel EYA1 mutation presenting in a newborn with laryngomalacia, glossoptosis, retrognathia, and pectus excavatum. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16691597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16691597</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16691597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31285" target="_blank">Full Text</a>]
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<a id="Stockley2009" class="mim-anchor"></a>
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Stockley, T. L., Mendoza-Londono, R., Propst, E. J., Sodhi, S., Dupuis, L., Papsin, B. C.
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<strong>A recurrent EYA1 mutation causing alternative RNA splicing in branchio-oto-renal syndrome: implications for molecular diagnostics and disease mechanism.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206155</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32679" target="_blank">Full Text</a>]
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Tootle, T. L., Silver, S. J., Davies, E. L., Newman, V., Latek, R. R., Mills, I. A., Selengut, J. D., Parlikar, B. E. W., Rebay, I.
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<strong>The transcription factor Eyes absent is a protein tyrosine phosphatase.</strong>
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Nature 426: 299-302, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628053</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628053" 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/nature02097" target="_blank">Full Text</a>]
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<a id="Vervoort2002" class="mim-anchor"></a>
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Vervoort, V. S., Smith, R. J. H., O'Brien, J., Schroer, R., Abbott, A., Stevenson, R. E., Schwartz, C. E.
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<strong>Genomic rearrangements of EYA1 account for a large fraction of families with BOR syndrome.</strong>
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Europ. J. Hum. Genet. 10: 757-766, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404110</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12404110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200877" target="_blank">Full Text</a>]
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Vincent, C., Kalatzis, V., Abdelhak, S., Chaib, H., Compain, S., Helia, J., Vaneecloo, F.-M., Petit, C.
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<strong>BOR and BO syndromes are allelic defects of EYA1.</strong>
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Europ. J. Hum. Genet. 5: 242-246, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9359046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9359046</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9359046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Xu, P.-X., Adams, J., Peters, H., Brown, M. C., Heaney, S., Maas, R.
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<strong>Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia.</strong>
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Nature Genet. 23: 113-117, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471511" 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/10.1038/12722" target="_blank">Full Text</a>]
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Xu, P.-X., Cheng, J., Epstein, J. A., Maas, R. L.
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<strong>Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function.</strong>
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Proc. Nat. Acad. Sci. 94: 11974-11979, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342347</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342347[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=9342347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.94.22.11974" target="_blank">Full Text</a>]
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Xu, P.-X., Woo, I., Her, H., Beier, D. R., Maas, R. L.
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<strong>Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode.</strong>
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Development 124: 219-231, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9006082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9006082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9006082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1242/dev.124.1.219" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 12/5/2013
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Cassandra L. Kniffin - updated : 2/16/2010<br>Ada Hamosh - updated : 4/21/2009<br>Cassandra L. Kniffin - updated : 7/22/2008<br>Cassandra L. Kniffin - updated : 5/6/2008<br>Victor A. McKusick - updated : 3/27/2007<br>Ada Hamosh - updated : 1/26/2007<br>Cassandra L. Kniffin - updated : 9/28/2006<br>Cassandra L. Kniffin - updated : 8/1/2006<br>Victor A. McKusick - updated : 3/28/2006<br>Victor A. McKusick - updated : 4/28/2005<br>Patricia A. Hartz - updated : 8/16/2004<br>Victor A. McKusick - updated : 6/15/2004<br>Marla J. F. O'Neill - updated : 3/24/2004<br>Ada Hamosh - updated : 12/31/2003<br>Victor A. McKusick - updated : 10/1/2003<br>Dawn Watkins-Chow - updated : 7/18/2003<br>George E. Tiller - updated : 6/7/2002<br>Michael J. Wright - updated : 8/8/2001<br>Victor A. McKusick - updated : 3/7/2000<br>Victor A. McKusick - updated : 8/26/1999<br>Wilson H. Y. Lo - updated : 7/14/1999<br>Victor A. McKusick - updated : 5/14/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Victor A. McKusick - updated : 9/9/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Victor A. McKusick - updated : 10/30/1997
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Victor A. McKusick : 2/2/1997
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alopez : 03/21/2024
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carol : 01/23/2024<br>carol : 09/19/2019<br>carol : 02/04/2016<br>alopez : 12/5/2014<br>carol : 12/4/2014<br>carol : 12/5/2013<br>carol : 10/1/2013<br>alopez : 12/11/2012<br>alopez : 12/11/2012<br>carol : 5/8/2012<br>wwang : 2/18/2010<br>ckniffin : 2/16/2010<br>alopez : 4/21/2009<br>wwang : 7/29/2008<br>ckniffin : 7/22/2008<br>wwang : 5/12/2008<br>ckniffin : 5/6/2008<br>alopez : 3/29/2007<br>terry : 3/27/2007<br>alopez : 1/26/2007<br>carol : 10/18/2006<br>ckniffin : 10/18/2006<br>ckniffin : 9/28/2006<br>carol : 8/2/2006<br>ckniffin : 8/1/2006<br>alopez : 3/30/2006<br>terry : 3/28/2006<br>tkritzer : 5/12/2005<br>terry : 4/28/2005<br>terry : 3/3/2005<br>mgross : 9/7/2004<br>terry : 8/16/2004<br>tkritzer : 6/23/2004<br>terry : 6/15/2004<br>tkritzer : 3/30/2004<br>terry : 3/24/2004<br>alopez : 1/8/2004<br>terry : 12/31/2003<br>alopez : 11/25/2003<br>alopez : 10/31/2003<br>alopez : 10/1/2003<br>terry : 10/1/2003<br>tkritzer : 8/21/2003<br>tkritzer : 8/20/2003<br>terry : 7/18/2003<br>cwells : 9/3/2002<br>cwells : 6/12/2002<br>cwells : 6/7/2002<br>cwells : 8/16/2001<br>cwells : 8/9/2001<br>terry : 8/8/2001<br>terry : 1/22/2001<br>mcapotos : 4/3/2000<br>mcapotos : 3/17/2000<br>terry : 3/7/2000<br>alopez : 8/30/1999<br>mgross : 8/27/1999<br>terry : 8/26/1999<br>carol : 7/16/1999<br>kayiaros : 7/14/1999<br>mgross : 5/27/1999<br>mgross : 5/20/1999<br>terry : 5/14/1999<br>carol : 2/6/1999<br>terry : 2/3/1999<br>carol : 10/19/1998<br>dkim : 9/10/1998<br>alopez : 9/10/1998<br>terry : 9/9/1998<br>dholmes : 1/23/1998<br>mark : 1/2/1998<br>terry : 12/19/1997<br>jenny : 11/5/1997<br>terry : 10/30/1997<br>mark : 6/20/1997<br>mark : 2/2/1997<br>mark : 2/2/1997<br>terry : 1/31/1997<br>mark : 1/31/1997
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<span class="mim-font">
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<strong>*</strong> 601653
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<h3>
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EYA TRANSCRIPTIONAL COACTIVATOR AND PHOSPHATASE 1; EYA1
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</h3>
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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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EYES ABSENT 1<br />
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EYES ABSENT, DROSOPHILA, HOMOLOG OF, 1
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</h4>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: EYA1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 429448005;
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<strong>
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<em>
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Cytogenetic location: 8q13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:71,197,433-71,548,094 </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>
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</p>
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<h4>
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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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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="4">
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<span class="mim-font">
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8q13.3
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<td>
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<span class="mim-font">
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?Otofaciocervical syndrome
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<span class="mim-font">
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166780
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<span class="mim-font">
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Autosomal dominant
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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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Anterior segment anomalies with or without cataract
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</span>
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</td>
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<span class="mim-font">
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602588
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<span class="mim-font">
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Autosomal dominant
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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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Branchiootic syndrome 1
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<span class="mim-font">
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602588
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<span class="mim-font">
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Autosomal dominant
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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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Branchiootorenal syndrome 1, with or without cataracts
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</td>
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<td>
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<span class="mim-font">
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113650
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<span class="mim-font">
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Autosomal dominant
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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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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Members of the EYA family, including EYA1, have protein phosphatase function, and EYA enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation (summary by Li et al., 2003). </p>
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</span>
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<div>
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<br />
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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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</h4>
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<p>By positional cloning in the 8q13.3 region where the branchiootorenal dysplasia syndrome (BOR; 113650) maps, Abdelhak et al. (1997) identified a gene that they showed to be responsible for the disorder. The gene is a human homolog of the Drosophila 'eyes absent' gene (Eya) and was therefore called EYA1. The gene encodes a deduced 559-amino acid polypeptide with a predicted molecular mass of 61.2 kD. Abdelhak et al. (1997) also found a highly conserved 271-amino acid C-terminal region in the products of 2 other human genes, which were subsequently called EYA2 (601654) and EYA3 (601655), demonstrating the existence of a novel gene family. </p><p>Li et al. (2003) showed that EYA1 encodes a dual-function transcription factor with an N-terminal transcriptional coactivator region and a C-terminal dephosphorylation domain. </p>
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</span>
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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>Abdelhak et al. (1997) studied the expression pattern of the mouse EYA1 ortholog and obtained results suggesting a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern indicated a role for Eya1 in the metanephric cells surrounding the 'just-divided' ureteric branches. </p><p>Xu et al. (1997) showed that in the limbs of 10.5-day mouse embryos, Eya1 expression was largely restricted to the flexor tendons, whereas Eya2 (601654) was expressed in the extensor tendons and probably also in the ligaments of the phalanges. They demonstrated that the proline/serine/threonine-rich N-terminal regions of the protein products of the Eya1, Eya2, and Eya3 (601655) genes have transcriptional activator activity. These results supported a role for the Eya genes in connective tissue patterning in the limbs. </p><p>Azuma et al. (2000) stated that in Drosophila, the Eya gene is involved in the formation of compound eyes. Flies with loss-of-function mutations of this gene develop no eyes and form ectopic eyes in the antennae and the ventral zone of the head on target expression. A highly conserved homologous gene in various invertebrates and vertebrates has been shown to function in the formation of the eye. </p><p>Using sequence analysis, Hsiao et al. (2001) identified 2 conserved mitogen-activated protein kinase (MAPK) sites in the EYA1 sequence. In vivo genetic analysis, together with in vitro kinase assay results, demonstrated that Eya is a substrate for extracellular signal-regulated kinase, the MAPK acting downstream in the receptor tyrosine kinase (RTK) signaling pathway. Hsiao et al. (2001) hypothesized that phosphorylation of Drosophila Eya provides a direct regulatory link between the RTK/Ras/MAPK signaling cascade and the retinal determination gene network. They concluded that Eya function in Drosophila is positively regulated by MAPK-mediated phosphorylation. </p><p>Buller et al. (2001) analyzed the functional importance of Eya domain missense mutations with respect to protein complex formation and cellular localization. Previously described point mutations did not alter protein localization; however, 3 mutations (glu330 to lys, 601653.0009; ser454 to pro, 601653.0012; and leu472 to arg, 601653.0013) disrupted interactions between Eya and the sine oculis homeobox protein (Six1; 601125) in both yeast and mammalian cells. Binding to Six2 (604994) was not impeded. </p><p>Rayapureddi et al. (2003) demonstrated that Eya is a protein-tyrosine phosphatase in Drosophila. It does not resemble the classical tyrosine phosphatases that use cysteine as a nucleophile and proceed by means of a thiol-phosphate intermediate. Rather, Eya is the prototype for a class of protein-tyrosine phosphatases that use a nucleophilic aspartic acid in a metal-dependent reaction. Furthermore, Rayapureddi et al. (2003) showed that the phosphatase activity of Eya contributes to its ability to induce eye formation in Drosophila. </p><p>Tootle et al. (2003) independently showed that Eya belongs to the phosphatase subgroup of the haloacid dehalogenase (HAD) superfamily, and proposed a function for it as a non-thiol-based protein-tyrosine phosphatase. Experiments performed in cultured Drosophila cells and in vitro indicated that Eya has intrinsic protein-tyrosine phosphatase activity and can autocatalytically dephosphorylate itself. Confirming the biologic significance of this function, mutations that disrupt the phosphatase active site severely compromise the ability of Eya to promote eye specification and development in Drosophila. Tootle et al. (2003) concluded that given the functional importance of phosphorylation-dependent modulation of transcription factor activity, this evidence for a nuclear transcriptional coactivator with intrinsic phosphatase activity suggests an unanticipated method of fine-tuning transcriptional regulation. </p><p>Grifone et al. (2004) found that among the Six and Eya gene products expressed in mouse skeletal muscle, Six1 and Eya1 accumulated preferentially in the nuclei of fast-twitch muscles. Forced coexpression of Six1 and Eya1 in the slow-twitch soleus muscle induced a transition to a fast-twitch fiber type, with activation of fast-twitch fiber-specific genes and a switch toward glycolytic metabolism. </p><p>Alkuraya et al. (2006) identified EYA1 as a substrate for sumoylation with SUMO1 (601912) in vivo. This was confirmed by abolishing the sumoylated Eya1 species with a SUMO-specific peptidase, SENP1. Furthermore, an Eya1 mutant protein in which 2 of 3 predicted high probability lysine residues were replaced with arginine displayed minimal sumoylation. In mice haploinsufficient for both Sumo1 and Eya1, the incidence of cleft lip/palate (36%) was significantly increased compared with that in mice haploinsufficient for Sumo1 (8.7%) or Eya1 (0.0%) alone. </p><p>Cook et al. (2009) reported that the protein-tyrosine phosphatase EYA is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in mammalian embryonic kidney cells by executing a damage signal-dependent dephosphorylation of an H2AX (601772) carboxy-terminal tyrosine phosphate (Y142). This posttranslational modification determines the relative recruitment of either DNA repair or proapoptotic factors to the tail of serine-phosphorylated histone H2AX and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis. </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>Gene Structure</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Abdelhak et al. (1997) reported the complete genomic structure of the EYA1 gene. The gene consists of 16 coding exons and extends over 156 kb. It encodes various alternatively spliced transcripts differing only in their 5-prime regions. </p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Branchiootorenal Syndrome 1</em></strong></p><p>
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To test for possible DNA rearrangements within EYA1 in BOR probands, Abdelhak et al. (1997) hybridized Southern blots containing DNA from 21 familial and sporadic patients with probes corresponding to exons A to G of the gene and the exon immediately adjacent to exon A (designated exon z). In a sporadic case of BOR, hybridization with exon D resulted in a signal of reduced intensity, suggesting a deletion; this reduction was not seen in the proband's parents. Hybridization with exons A and B resulted in signals of normal intensity, C resulted in a band shift, and E, F, and G resulted in bands of reduced intensity. It was estimated that the deletion in this individual spanned 5.8 to 7 kb. In another patient, Abdelhak et al. (1997) detected a premature stop codon in exon z (601653.0001); in a third patient, replacement of a T with CC insertion was detected in exon D (601653.0002). The affected family members of these 2 probands carried the same mutations, whereas the unaffected family members did not. In a fourth patient, a 1-bp insertion was detected in exon c. The phenotypically normal parent of this proband did not carry this mutation. In each of 4 other individuals, a mutation was detected. </p><p>Abdelhak et al. (1997) performed sequence analysis of the entire EYA1 coding region for 20 unrelated patients affected by BOR syndrome, and 6 novel mutations were identified. Sequence analysis of the coding region, including splice site junctions, as well as Southern blot analysis of the coding region and the 5-prime and 3-prime untranslated regions (UTRs), failed to detect anomalies in 14 of the 20 patients. Among these 14 patients, 10 represented familial cases, and, for 6 of them, linkage analysis was consistent with the involvement of EYA1. Since no evidence for genetic heterogeneity had been reported, Abdelhak et al. (1997) assumed that, for these 14 patients, the mutations were located either in the promoter region, within an intron, in the 3-prime UTR, or in the most 5-prime sequences which had not yet been studied extensively. This report brought the total number of mutations detected in BOR patients to 14; all of them were different. A common feature of the mutations, however, was their location within or in the immediate vicinity of the eyaHR (also called Eya box). The region of clustering of mutations represents half of the coding sequence. Mutations outside this domain may give rise to either a lethal defect or to a discrete undetected phenotype. Abdelhak et al. (1997) favored the latter hypothesis for the following reasons: 1 of the 2 patients carrying a deletion of the whole gene was exclusively affected by the BO syndrome (Haan et al., 1989), and the only mutation that had been detected outside the eyaHR was also present in a BOR-affected patient (601653.0004). </p><p>Kumar et al. (1998) identified 3 novel mutations in the EYA1 gene in patients with the BOR syndrome, 1 of which was a 4-bp deletion in a family originally reported by Rowley (1969). Kumar et al. (1998) found reports of 20 mutations in the EYA1 gene, most of them clustered in the C-terminal region (exons 9 to 16), in cases of BOR syndrome. Rickard et al. (2000) identified mutations in 11 of 18 individuals with classic BOR. They found no mutations in individuals with atypical BOR syndrome or OTFC syndrome. The mutations identified were clustered in exons 9 to 16 with 3 in exon 8 and 1 in exon 5. </p><p>Vervoort et al. (2002) noted that in up to one-half of reported cases of BOR syndrome, EYA1 screening was negative, suggesting genetic heterogeneity. Using SSCP and direct sequencing, they screened the coding region of the EYA1 gene in a panel of BOR families linked to chromosome 8. Only 1 point mutation in 5 probands was detected. However, using Southern blot analysis, complex rearrangements such as inversions and large deletions were identified in the other 4 patients. Vervoort et al. (2002) concluded that more complex rearrangements may have been missed in earlier studies, which commonly used only SSCP and sequencing for mutation detection. </p><p>Chang et al. (2004) sought to refine the clinical diagnosis of BOR syndrome by analyzing phenotypic data from families segregating EYA1 disease-causing mutations. Based on genotype-phenotype analyses, they proposed new criteria for the clinical diagnosis of BOR syndrome. The authors found that in approximately 40% of patients meeting their criteria, EYA1 mutations were identified. Of these mutations, 80% were coding sequence variants identified by SSCP, and 20% were complex genomic rearrangements identified by a semiquantitative PCR-based screen. Chang et al. (2004) concluded that genetic testing of EYA1 should include analysis of the coding sequence and a screen for complex rearrangements. </p><p>Migliosi et al. (2004) used an analysis based on denaturing high performance liquid chromatography (DHPLC) to identify 5 novel mutations in the EYA1 gene associated with BOR syndrome. </p><p>Orten et al. (2008) identified 70 different EYA1 mutations in 89 of 435 families with BOR or a related phenotype. EYA1 mutations were found in 76 (31%) of 248 families fitting established clinical criteria for BOR and 13 (7%) of 187 families with a questionable BOR phenotype. Most of the mutations were private, and there were no apparent genotype/phenotype correlations. </p><p>Stockley et al. (2009) identified EYA1 mutations (see, e.g., 601653.0016) in 14 (82%) of 17 unrelated probands with BOR syndrome. De novo mutations were confirmed in 45% of the patients. </p><p>In a patient carrying a mutation in the SIX5 gene (T552M; 600963.0004), Krug et al. (2011) identified a mutation in the EYA1 gene, a deletion removing exons 3, 4, and 5. This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This observation, in addition to the extreme rarity of SIX5 mutations, caused Krug et al. (2011) to reconsider the role of SIX5 in branchiootorenal syndrome etiology. </p><p><strong><em>Branchiootic Syndrome 1</em></strong></p><p>
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To address the question of whether the branchiootic syndrome (BOS1; 602588) is the same as branchiootorenal dysplasia, Vincent et al. (1997) studied 2 large kindreds in each of which 8 affected members presented exclusively with BO syndrome (without the association of renal anomalies). In both kindreds, linkage analysis mapped the causative gene to the same chromosomal region as the EYA1 gene. A search for mutations in 9 of the EYA1 coding exons identified a 2-bp insertion (601653.0003) segregating in 1 family, and an 8-bp deletion (601053.0004) segregating in the other. Thus, the BOR and BO syndromes are allelic defects in the EYA1 gene. </p><p><strong><em>Anterior Segment Anomalies</em></strong></p><p>
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Azuma et al. (2000) examined genomic DNA isolated from patients with various types of developmental eye anomalies for EYA1 mutations by the use of PCR-SSCP and sequencing. They identified 3 novel missense mutations in patients who had congenital cataracts and ocular anterior segment anomalies (see 601653.0008-601653.0010). One of the patients had clinical features of BOR syndrome as well (see 601653.0010). These results implied that the human EYA1 gene is also involved in eye morphogenesis, and that a wide variety of clinical manifestations may be caused by EYA mutations. Mutations were heterozygous in all 3 probands; 2 of the 3 were sporadic. </p><p><strong><em>Otofaciocervical Syndrome</em></strong></p><p>
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Rickard et al. (2001) presented evidence that the otofaciocervical syndrome (OTFCS1; 166780) is a contiguous gene deletion syndrome involving the EYA1 gene, which is the site of mutations causing the branchiootorenal syndrome. They speculated that the differences between the 2 syndromes might be related to undefined genes included in the deleted region accounting for additional traits seen in OTFCS. Estefania et al. (2006) reported a patient with a splice site mutation in the EYA1 gene (601653.0014) and clinical changes thought to be characteristic of OTFCS, namely, alterations of the face and shoulder girdle in addition to malformations seen in BOR. </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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Johnson et al. (1999) described a spontaneous mutation causing deafness and circling behavior in a C3H/HeJ colony of mice. Pathologic analysis of mutant mice showed gross morphologic abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior were shown to be inherited as an autosomal recessive trait, and were mapped to chromosome 1, near the position of the Eya1 gene (Xu et al., 1997). Molecular analysis of the Eya1 gene in mutant mice revealed insertion of an intracisternal A particle (IAP) element in intron 7. The presence of the IAP insertion was associated with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. Johnson et al. (1999) designated the new mouse mutation Eya1(bor) to denote that it appears to be an authentic model of the human BOR syndrome. </p><p>In mice, Floyd et al. (2003) studied the modifier-of-vibrator-1 locus (Mvb1), which controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, such as occurs in the Eya1(BOR) model of human branchiootorenal syndrome. By positional complementation cloning, they identified Mvb1 as the nuclear export factor Nxf1 (602647), providing an unexpected link between the mRNA export receptor and pre-mRNA processing. </p><p>To understand the developmental pathogenesis of organs affected in BOR syndrome and BO syndrome, Xu et al. (1999) inactivated the Eya1 gene in mice. Eya1 heterozygotes showed renal abnormalities and a conductive hearing loss similar to BOR syndrome, whereas Eya1 homozygotes lacked ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia. Inner ear development in Eya1 homozygotes arrested at the otic vesicle stage, and all components of the inner ear and specific cranial sensory ganglia failed to form. In the kidney, Eya1 homozygosity resulted in an absence of ureteric bud outgrowth and a subsequent failure of metanephric induction. Gdnf (600837) expression, which is required to direct ureteric bud outgrowth via activation of the RET receptor tyrosine kinase (164761), was not detected in Eya1 -/- metanephric mesenchyme. In Eya1 -/- ear and kidney development, Six (see SIX1; 601205) but not Pax (see PAX2; 167409) expression was Eya1 dependent, similar to a genetic pathway elucidated in the Drosophila eye imaginal disc. The results indicated that EYA1 controls critical early inductive signaling events involved in ear and kidney formation, and integrated EYA1 into the genetic regulatory cascade controlling kidney formation upstream of GDNF. In addition, the results suggested that an evolutionarily conserved PAX-EYA-SIX regulatory hierarchy is used in mammalian ear and kidney development. </p><p>Li et al. (2003) reported that Six1 is required for the development of murine kidney, muscle, and inner ear and that it exhibits synergistic genetic interactions with Eya factors. Li et al. (2003) demonstrated that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach (603803) from repression to activation, causing transcriptional activation through recruitment of coactivators. The gene-specific recruitment of a coactivator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis. Eya1 +/- Six1 +/- double heterozygous mice had a defect in kidney development, which was not observed in single heterozygotes for either gene deletion, suggesting that Six1 and Eya1 act in the same genetic pathway. Notably, there was a complete absence of all hypaxial muscle in Six1 -/- Eya1 -/- double knockout mice and severe reduction of epaxial muscle, a phenotype resembling that seen in mice homozygous for deletion of Myog (159980) and in double knockouts for MyoD (159970)/Myf5 (159990) and Pax3 (606597)/Myf5. Interestingly, although mutation of Six1 or Eya1 has minimal or no effect on pituitary development, mice with both genes deleted have a pituitary that is approximately 5- to 10-fold smaller by volume than the wildtype gland. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>17 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 BRANCHIOOTORENAL SYNDROME 1</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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EYA1, ARG275TER
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<br />
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SNP: rs121909195,
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gnomAD: rs121909195,
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ClinVar: RCV000008391, RCV000844696, RCV001851734, RCV002259304, RCV003390657, RCV005049321
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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 familial case of BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) demonstrated a C-to-T transition of nucleotide 823 in exon z, resulting in a change of codon 275 from arginine to stop. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 BRANCHIOOTORENAL SYNDROME 1</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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EYA1, 1-BP DEL AND 2-BP INS, 1251T-CC
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<br />
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ClinVar: RCV000008392
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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 familial case of BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) demonstrated substitution of 1251T with CC in exon D, resulting in a frameshift and premature termination of transcription. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 BRANCHIOOTIC SYNDROME 1</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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EYA1, 2-BP INS, 870GT
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<br />
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ClinVar: RCV000008393
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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 kindred in which 8 members in 3 generations had the branchiootic syndrome (BOS1; 602588) (without renal anomalies), Vincent et al. (1997) demonstrated linkage to the same region of chromosome 8 where the EYA1 gene is located. Furthermore, they demonstrated a 2-bp (GT) insertion in exon A, at position 870. </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 BRANCHIOOTIC SYNDROME 1</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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EYA1, 8-BP DEL, NT297
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<br />
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ClinVar: RCV000008394
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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 8 living members in 3 generations showing BO syndrome (BOS1; 602588), Vincent et al. (1997) demonstrated an 8-bp deletion at position 297 (297del8) of the EYA1 gene. The mutation resulted in a frameshift leading to a premature stop codon. </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 BRANCHIOOTORENAL SYNDROME 1</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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EYA1, ALU INS, EX10
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<br />
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ClinVar: RCV000008395
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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 mother and daughter with BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) demonstrated that the EYA1 gene carried an inserted Alu element in exon 10. The inserted element was in opposite orientation to that of the gene itself, and the 3-prime sequence of the Alu element was followed by a long poly(A) tail. The features were entirely consistent with retrotransposition. A difference in length of the poly(A) tail, which was reduced from poly(A)97 to poly(A)31 when transmitted from mother to daughter, demonstrated instability. The transposition was a de novo insertion as it was not present in the DNA from the maternal grandparents. </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 BRANCHIOOTORENAL SYNDROME 1</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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EYA1, 4-BP DEL, NT1501
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<br />
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SNP: rs606231355,
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ClinVar: RCV000008396
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a family reported originally by Rowley (1969), Kumar et al. (1998) demonstrated association of the BOR syndrome (BOR1; 113650) with a 4-bp deletion at nucleotide 1501 of the EYA1 gene. </p>
|
|
</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 BRANCHIOOTORENAL SYNDROME 1</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
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EYA1, ARG407GLN
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<br />
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|
|
SNP: rs121909196,
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|
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ClinVar: RCV000008397, RCV000844628, RCV001849260, RCV002228019, RCV002288475, RCV004739295, RCV004795383
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</span>
|
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</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of familial BOR syndrome (BOR1; 113650), Kumar et al. (1998) identified a G-to-A transition at nucleotide 1220 in exon 12, resulting in an arg407-to-gln substitution. </p>
|
|
</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 ANTERIOR SEGMENT ANOMALIES AND CATARACT</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
EYA1, ARG514GLY
|
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|
|
<br />
|
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|
|
SNP: rs121909197,
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|
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|
|
ClinVar: RCV000008398
|
|
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|
|
</span>
|
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</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-year-old Japanese girl with congenital cataracts and ocular anterior segment anomalies (see BOS1, 602588), Azuma et al. (2000) found an A-to-G transition at position 1688 of the cDNA corresponding to the EYA1 gene, expected to result in an arg514-to-gly amino acid substitution. Ocular examinations revealed central corneal opacity, adhesion to the iris (Peters anomaly), and slight cataracts in both eyes, whereas the fundus was normal. Her mother, aged 32, had nuclear-type congenital cataracts. The patient and her mother were otherwise normal in appearance, intelligence, and karyotype. No clinical findings suggesting BO/BOR syndrome were detected except for a slight elevation of the auditory brainstem response (ABR) threshold in hearing. </p>
|
|
</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 ANTERIOR SEGMENT ANOMALIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
EYA1, GLU330LYS
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<br />
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|
|
SNP: rs121909198,
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|
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ClinVar: RCV000008399
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old Japanese boy with an iris anomaly (see BOS1, 602588), Azuma et al. (2000) found a glu330-to-lys mutation due to a G-to-A transition at position 1136 (exon 10) of the EYA1 gene. The mutation was not detected in his parents, who were apparently normal. Examinations revealed bilateral persistence of the pupillary membrane, but a normal lens and fundus. He had no other systemic abnormalities and was found to be normal in growth and intelligence for his age. </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>.0010 BRANCHIOOTORENAL SYNDROME WITH CATARACT</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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EYA1, GLY393SER
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<br />
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|
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SNP: rs121909199,
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|
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gnomAD: rs121909199,
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ClinVar: RCV000008400, RCV000309264, RCV000367199, RCV000496093, RCV000606853, RCV000657911, RCV004619188, RCV005089208
|
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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>Azuma et al. (2000) identified a gly393-to-ser mutation in an 8-year-old boy who first presented at their hospital with nystagmus and systemic edema at 20 days of age. Examinations revealed bilateral nuclear-type congenital cataracts with a normal fundus, and multicystic dysplasia in his right kidney, which did not function and caused hypocalcemia. The cataracts were operated on at 1 month of age and the right kidney was removed at 2 months. He was later found to have conductive deafness with the malleus anomaly. He also had cervical fistula that occluded spontaneously. Except for the cataracts, the clinical findings were considered typical of BOR syndrome (BOR1; 113650). </p>
|
|
</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>.0011 BRANCHIOOTORENAL SYNDROME 1</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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EYA1, 1-BP INS, 387T
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<br />
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ClinVar: RCV000008401
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with classic BOR syndrome (BOR1; 113650) with a single kidney, Rickard et al. (2000) identified a 1-bp insertion at nucleotide 387 in exon 5 of the EYA1 gene. The authors concluded that mutations located outside exons 9 to 16 do not appear to result in different renal manifestations. </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>.0012 BRANCHIOOTORENAL SYNDROME 1</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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EYA1, SER454PRO
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<br />
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SNP: rs121909200,
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gnomAD: rs121909200,
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ClinVar: RCV000008402, RCV003593858, RCV004739296
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a family with BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) identified a ser454-to-pro (S454P) mutation in exon 13 of the EYA1 gene. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 BRANCHIOOTORENAL SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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EYA1, LEU472ARG
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<br />
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SNP: rs121909201,
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ClinVar: RCV000008403
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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 BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) identified a leu472-to-arg (L472R) mutation in exon 14 of the EYA1 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 OTOFACIOCERVICAL SYNDROME 1 (1 patient)</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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EYA1, IVS6DS, G-A, +1
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<br />
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SNP: rs869025180,
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ClinVar: RCV000008404, RCV002512904
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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 patient thought to have otofaciocervical syndrome (OFC1; 166780), Estefania et al. (2006) found a de novo heterozygous nucleotide substitution at the beginning of intron 6 of the EYA1 gene (540+1G-A). The patient had bilateral conductive hearing loss, a long and narrow face, preauricular and cervical pits, prominent and cupped ears, a high-arched palate, sloping shoulders and clavicles, and trapezius hypoplasia which allowed adduction of the shoulders. Chest x-ray showed diastasis of the right sternoclavicular joint, and urography demonstrated bilateral sponge kidneys. </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>.0015 BRANCHIOOTIC SYNDROME 1</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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BRANCHIOOTORENAL SYNDROME 1, 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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EYA1, ARG328TER
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<br />
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SNP: rs121909202,
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gnomAD: rs121909202,
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ClinVar: RCV000008405, RCV000008406, RCV001823094, RCV002228020, RCV002512905, RCV004554585, RCV005042015
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an infant with a variant form of branchiootic syndrome (BOS1; 602588), Spruijt et al. (2006) identified a heterozygous 982C-T transition in exon 10 of the EYA1 gene, resulting in an arg328-to-ter (R328X) substitution predicted to lead to a nonfunctional protein. The patient had severe obstructive sleep apnea caused by laryngomalacia, pharyngomalacia, glossoptosis, and tracheobronchomalacia. He also had retrognathia, bilateral branchial fistulae, ear anomalies, including ear pits, simple helices, and slight cup-shaped and low-set left ear. His mother, who also carried the mutation, had mild retrognathia, left-sided branchial neck fistula, left-sided preauricular pit, and right-sided branchial cyst in the neck. Kidney ultrasound and hearing were normal in both the mother and son. The findings expanded the phenotypic anomalies of BO syndrome associated with EYA1 mutations. </p><p>Olavarrieta et al. (2008) identified a de novo R328X mutation in the EYA1 gene in a Spanish man with branchiootorenal syndrome (BOR1; 113650). He had branchial fistulae, preauricular pits, renal agenesis, and mixed hearing loss. In addition, he had myopia, vitreous anomaly, flat face, and cleft palate, characteristic of Stickler syndrome type I (STL1; 108300) and was found to also carry a mutation in the COL2A1 gene (120140). Olavarrieta et al. (2008) emphasized that both disorders show phenotypic variability as well as overlapping features, which can complicate a precise diagnosis. Thorough clinical evaluation is necessary to identify coexisting genetic syndromes in the same patient. </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>.0016 BRANCHIOOTIC SYNDROME 1</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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EYA1, 7-BP DEL, NT1402
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<br />
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SNP: rs606231356,
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ClinVar: RCV000008407
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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 Japanese girl with features of the branchiootic syndrome (BOS1; 602588), Shimasaki et al. (2004) identified a heterozygous 7-bp deletion (1402delACAACTA) in exon 14 of the EYA1 gene, resulting in a frameshift and premature termination of the protein at codon 483. The child had preauricular pits, cupped ears, hearing loss, and bilateral cysts over the sternocleid muscle. The mutation was most likely transmitted by the mother, who also had features of the branchiootic syndrome, although this was not confirmed by molecular testing. The patient also had features consistent with the Cayler cardiofacial syndrome (125520), including asymmetric facies while crying and a large patent ductus arteriosus. Shimasaki et al. (2004) suggested that the BO syndrome and Cayler syndrome may represent a spectrum of diseases. </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>.0017 BRANCHIOOTORENAL SYNDROME 1</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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EYA1, IVS8DS, G-A, +5
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<br />
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SNP: rs606231357,
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ClinVar: RCV000008408, RCV001569391, RCV001851735
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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 affected members of 3 of 17 unrelated families with BOR syndrome (BOR1; 113650), Stockley et al. (2009) identified a heterozygous G-to-A transition in intron 8 of the EYA1 gene (867+5G-A), resulting in a transcript lacking exon 8, predicting a frameshift and premature termination within exon 9. The mutation was not found in 100 control chromosomes. The same mutation was also found in 2 additional unrelated BOR probands outside of the original cohort. Haplotype analysis did not indicate a founder effect. RT-PCR analysis showed that the transcript produced by the splice site mutation escaped nonsense-mediated mRNA decay and produced a truncated protein containing only the N-terminal coactivator region, but not the C-terminal phosphatase domain. Stockley et al. (2009) suggested that this resulted in a combination of dominant-negative gain of function and haploinsufficiency. The renal phenotype was severe in affected individuals, including renal agenesis, structural abnormalities, and renal artery dysplasia. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Levi-Acobas, F., Cruaud, C., Le Merrer, M., Mathieu, M., Konig, R., Vigneron, J., Weissenbach, J., Petit, C., Weil, D.
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<strong>Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.</strong>
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Hum. Molec. Genet. 6: 2247-2255, 1997.
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<li>
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<p class="mim-text-font">
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|
Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C.
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<strong>A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.</strong>
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Nature Genet. 15: 157-164, 1997.
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<li>
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<p class="mim-text-font">
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Alkuraya, F. S., Saadi, I., Lund, J. L., Turbe-Doan, A., Morton, C. C., Maas, R. L.
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<strong>SUMO1 haploinsufficiency leads to cleft lip and palate.</strong>
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Science 313: 1751 only, 2006.
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[PubMed: 16990542]
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<p class="mim-text-font">
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Azuma, N., Hirakiyama, A., Inoue, T., Asaka, A., Yamada, M.
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<strong>Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.</strong>
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Hum. Molec. Genet. 9: 363-366, 2000.
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[PubMed: 10655545]
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Buller, C., Xu, X., Marquis, V., Schwanke, R., Xu, P.-X.
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<strong>Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.</strong>
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Hum. Molec. Genet. 10: 2775-2781, 2001.
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[PubMed: 11734542]
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[Full Text: https://doi.org/10.1093/hmg/10.24.2775]
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Chang, E. H., Menezes, M., Meyer, N. C., Cucci, R. A., Vervoort, V. S., Schwartz, C. E., Smith, R. J. H.
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<strong>Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences.</strong>
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Hum. Mutat. 23: 582-589, 2004.
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Cook, P. J., Ju, B. G., Telese, F., Wang, X., Glass, C. K., Rosenfeld, M. G.
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<strong>Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.</strong>
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Nature 458: 591-596, 2009.
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<p class="mim-text-font">
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Estefania, E., Ramirez-Camacho, R., Gomar, M., Trinidad, A., Arellano, B., Garcia-Berrocal, J. R., Verdaguer, J. M., Vilches, C.
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<strong>Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome.</strong>
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<p class="mim-text-font">
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Floyd, J. A., Gold, D. A., Concepcion, D., Poon, T. H., Wang, X., Keithley, E., Chen, D., Ward, E. J., Chinn, S. B., Friedman, R. A., Yu, H.-T., Moriwaki, K., Shiroishi, T., Hamilton, B. A.
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<strong>A natural allele of Nxf1 suppresses retrovirus insertional mutations.</strong>
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<p class="mim-text-font">
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Grifone, R., Laclef, C., Spitz, F., Lopez, S., Demignon, J., Guidotti, J.-E., Kawakami, K., Xu, P.-X., Kelly, R., Petrof, B. J., Daegelen, D., Concordet, J.-P., Maire, P.
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<strong>Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype.</strong>
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<p class="mim-text-font">
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Haan, E. A., Hull, Y. J., White, S., Cockington, R., Charlton, P., Callen, D. F.
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<strong>Tricho-rhino-phalangeal and branchio-oto syndromes in a family with an inherited rearrangement of chromosome 8q.</strong>
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<p class="mim-text-font">
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Hsiao, F. C., Williams, A., Davies, E. L., Rebay, I.
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<strong>Eyes absent mediates cross-talk between retinal determination genes and the receptor tyrosine kinase signaling pathway.</strong>
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</p>
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<li>
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<p class="mim-text-font">
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Johnson, K. R., Cook, S. A., Erway, L. C., Matthews, A. N., Sanford, L. P., Paradies, N. E., Friedman, R. A.
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<strong>Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome.</strong>
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Hum. Molec. Genet. 8: 645-653, 1999.
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[PubMed: 10072433]
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[Full Text: https://doi.org/10.1093/hmg/8.4.645]
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<li>
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<p class="mim-text-font">
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Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L.
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<strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong>
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Hum. Mutat. 32: 183-190, 2011.
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[PubMed: 21280147]
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<p class="mim-text-font">
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Kumar, S., Deffenbacher, K., Cremers, C. W. R. J., Van Camp, G., Kimberling, W. J.
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<strong>Branchio-oto-renal syndrome: identification of novel mutations, molecular characterization, mutation distribution, and prospects for genetic testing.</strong>
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Genet. Test. 1: 243-251, 1998.
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[PubMed: 10464653]
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<p class="mim-text-font">
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Kumar, S., Kimberling, W. J., Weston, M. D., Schaefer, B. G., Berg, M. A., Marres, H. A. M., Cremers, C. W. R. J.
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<strong>Identification of three novel mutations in human EYA1 protein associated with branchio-oto-renal syndrome.</strong>
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Hum. Mutat. 11: 443-449, 1998.
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[PubMed: 9603436]
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[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:6<443::AID-HUMU4>3.0.CO;2-S]
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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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Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G.
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<strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong>
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Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.
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[PubMed: 14628042]
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[Full Text: https://doi.org/10.1038/nature02083]
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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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Migliosi, V., Flex, E., Guida, V., Martini, A., Giarbini, N., Markova, T., Torrente, I., Dallapiccola, B.
|
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<strong>Identification of five novel BOR mutations in human EYA1 gene associated with branchio-oto-renal syndrome by a DHPLC-based assay. (Letter)</strong>
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