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- *605646 - SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605646</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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/605646">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 role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</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 panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="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=ENSG00000091137;t=ENST00000644269" 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=5172" 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=605646" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000091137;t=ENST00000644269" 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_000441" 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_000441" 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=605646" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=05735&isoform_id=05735_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/SLC26A4" 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/2654005,4505697,6174895,41393484,41471240,119603820,221039978,221042268,221043270,913524347,1248647093,2028478941,2028478945" 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/O43511" 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=5172" 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=ENSG00000091137;t=ENST00000644269" 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=SLC26A4" 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=SLC26A4" 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+5172" 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/SLC26A4" 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:5172" 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/5172" 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=chr7&hgg_gene=ENST00000644269.2&hgg_start=107660828&hgg_end=107717809&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/genes/HGNC:8818" 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/slc26a4" 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=605646[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=605646[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://gnomad.broadinstitute.org/gene/ENSG00000091137" 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=SLC26A4" 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=SLC26A4" 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=SLC26A4" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://webh01.ua.ac.be/hhh/" title="Hereditary Hearing Loss Homepage" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Hereditary Hearing Loss Ho…</a></div><div style="margin-left: 0.5em;"><a href="https://research.cchmc.org/LOVD2/home.php?select_db=SLC26A4" title="CCHMC Molecular Genetics Laboratory Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC Molecular Genetics L…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SLC26A4&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/PA35506" 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:8818" 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/FBgn0036770.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:1346029" 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/SLC26A4#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:1346029" 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/5172/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=5172" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00012259;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00012259 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00013963;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00013963 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00017464;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00017464 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00020914;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00020914 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-060503-544" 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:5172" 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=SLC26A4&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> 70348004<br />
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<strong>ICD10CM:</strong> E07.1<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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605646
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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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SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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PENDRIN<br />
|
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PDS GENE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SLC26A4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SLC26A4</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/7/577?start=-3&limit=10&highlight=577">7q22.3</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:107660828-107717809&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'})">7:107,660,828-107,717,809</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=600791,274600" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/577?start=-3&limit=10&highlight=577">
|
|
7q22.3
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Deafness, autosomal recessive 4, with enlarged vestibular aqueduct
|
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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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<a href="/entry/600791"> 600791 </a>
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<p>The SLC26A4 gene encodes an anion transporter known as pendrin and is the gene mutant in Pendred syndrome (PDS; <a href="/entry/274600">274600</a>) and enlarged vestibular aqueduct (EVA; <a href="/entry/600791">600791</a>).</p>
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<p><a href="#16" class="mim-tip-reference" title="Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D. <strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong> Nature Genet. 17: 411-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398842</a>] [<a href="https://doi.org/10.1038/ng1297-411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398842">Everett et al. (1997)</a> used a positional cloning strategy to identify the gene mutated in Pendred syndrome, which had been mapped by linkage to chromosome 7q31. The PDS gene produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, called pendrin by the authors, is closely related to a number of sulfate transporters. <a href="#16" class="mim-tip-reference" title="Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D. <strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong> Nature Genet. 17: 411-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398842</a>] [<a href="https://doi.org/10.1038/ng1297-411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398842">Everett et al. (1997)</a> found that the PDS gene encodes a 780-amino acid (86-kD) protein. Sequences resembling that of human pendrin were found across a large taxonomic span, including animals, plants, and yeast, although the 2 closest relatives were the proteins encoded by the human DRA (<a href="/entry/126650">126650</a>) and DTDST (<a href="/entry/606718">606718</a>) genes. The proteins within this family are highly hydrophobic; for example, 57% of the amino acids within pendrin are hydrophobic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398842" 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 study of the structure of the DRA gene, which is mutant in congenital chloride diarrhea (CLD; <a href="/entry/214700">214700</a>), <a href="#20" class="mim-tip-reference" title="Haila, S., Hoglund, P., Scherer, S. W., Lee, J. R., Kristo, P., Coyle, B., Trembath, R., Holmberg, C., de la Chapelle, A., Kere, J. <strong>Genomic structure of the human congenital chloride diarrhea (CLD) gene.</strong> Gene 214: 87-93, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9729124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9729124</a>] [<a href="https://doi.org/10.1016/s0378-1119(98)00261-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9729124">Haila et al. (1998)</a> found that the PDS gene is highly homologous to the DRA gene, with a similar genomic structure, and that it was situated 3-prime of the DRA gene in the same BAC clone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9729124" 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="#39" class="mim-tip-reference" title="Scott, D. A., Wang, R., Kreman, T. M., Sheffield, V. C., Karniski, L. P. <strong>The Pendred syndrome gene encodes a chloride-iodide transport protein.</strong> Nature Genet. 21: 440-443, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192399</a>] [<a href="https://doi.org/10.1038/7783" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192399">Scott et al. (1999)</a> were unable to detect evidence of sulfate transport following expression of pendrin in Xenopus oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus. The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems. <a href="#39" class="mim-tip-reference" title="Scott, D. A., Wang, R., Kreman, T. M., Sheffield, V. C., Karniski, L. P. <strong>The Pendred syndrome gene encodes a chloride-iodide transport protein.</strong> Nature Genet. 21: 440-443, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192399</a>] [<a href="https://doi.org/10.1038/7783" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192399">Scott et al. (1999)</a> concluded that pendrin functions as a transporter of chloride and iodide, but not of sulfate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10192399" 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="#24" class="mim-tip-reference" title="Kraiem, Z., Heinrich, R., Sadeh, O., Shiloni, E., Nassir, E., Hazani, E., Glaser, B. <strong>Sulfate transport is not impaired in Pendred syndrome thyrocytes.</strong> J. Clin. Endocr. Metab. 84: 2574-2576, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10404839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10404839</a>] [<a href="https://doi.org/10.1210/jcem.84.7.5973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10404839">Kraiem et al. (1999)</a> tested sulfate transport in thyrocytes obtained from PDS patients and found that it was not defective. This suggested that pendrin in fact may not be a sulfate transporter and emphasized the importance of functional studies on this protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10404839" 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="Everett, L. A., Morsli, H., Wu, D. K., Green, E. D. <strong>Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear.</strong> Proc. Nat. Acad. Sci. 96: 9727-9732, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10449762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10449762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10449762[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.17.9727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10449762">Everett et al. (1999)</a> isolated the mouse ortholog of the PDS gene and performed RNA in situ hybridization on mouse inner ears (from 8 days postcoitum to postnatal day 5) to establish the expression pattern of Pds in the developing auditory and vestibular systems. Pds expression was detected throughout the endolymphatic duct and sac, in distinct areas of the utricle and saccule, and in the external sulcus region within the cochlea. This highly discrete expression pattern is unlike that of any other known gene and involves several regions thought to be important for endolymphatic fluid resorption in the inner ear, consistent with the putative functioning of pendrin as an anion transporter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10449762" 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="Bidart, J.-M., Mian, C., Lazar, V., Russo, D., Filetti, S., Caillou, B., Schlumberger, M. <strong>Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues.</strong> J. Clin. Endocr. Metab. 85: 2028-2033, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10843192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10843192</a>] [<a href="https://doi.org/10.1210/jcem.85.5.6519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10843192">Bidart et al. (2000)</a> studied pendrin expression and localization using real-time kinetic quantitative PCR and antipeptide antibodies, respectively, in normal, benign, and malignant human thyroid tissues. The results were then compared to those observed for sodium/iodide symporter (NIS) expression. In normal tissue, pendrin is localized at the apical pole of thyrocytes, in contrast to the basolateral location of NIS. Immunostaining for pendrin was heterogeneous both inside and among follicles. In hyperfunctioning adenomas, the PDS mRNA level was in the normal range, although immunohistochemical analysis showed strong staining in the majority of follicular cells. In hypofunctioning adenomas, mean PDS gene expression was similar to that detected in normal thyroid tissues, but pendrin immunostaining was highly variable. In thyroid carcinomas, PDS gene expression was dramatically decreased, and pendrin immunostaining was low and was positive only in rare tumor cells. This expression profile was similar to that observed for the NIS gene and its protein product. The authors concluded that pendrin is expressed at the apical membrane of thyrocytes and that PDS gene expression is decreased in thyroid carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10843192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Scott, D. A., Wang, R., Kreman, T. M., Andrews, M., McDonald, J. M., Bishop, J. R., Smith, R. J. H., Karniski, L. P., Sheffield, V. C. <strong>Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).</strong> Hum. Molec. Genet. 9: 1709-1715, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861298</a>] [<a href="https://doi.org/10.1093/hmg/9.11.1709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861298">Scott et al. (2000)</a> compared 3 common Pendred syndrome allele variants with 3 PDS mutations reported only in individuals with nonsyndromic hearing loss. The mutations associated with Pendred syndrome exhibited complete loss of pendrin-induced chloride and iodide transport, while alleles unique to patients with DFNB4 were able to transport both iodide and chloride, albeit at a much lower level than wildtype pendrin. The authors hypothesized that the residual level of anion transport was sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4, a form of deafness also caused by mutations in pendrin (see <a href="/entry/600791">600791</a>). They proposed a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Taylor, J. P., Metcalfe, R. A., Watson, P. F., Weetman, A. P., Trembath, R. C. <strong>Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome.</strong> J. Clin. Endocr. Metab. 87: 1778-1784, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932316</a>] [<a href="https://doi.org/10.1210/jcem.87.4.8435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932316">Taylor et al. (2002)</a> investigated the effect of 9 SLC26A4 missense mutations on pendrin localization and iodide transport. Transient expression of green fluorescent protein-tagged pendrin mutant constructs in mammalian cell lines demonstrated appropriate trafficking to the plasma membrane for only 2 mutants. The remaining SLC26A4 mutants appeared to be retained within the endoplasmic reticulum following transfection. Iodide efflux assays were performed. The results indicated loss of pendrin iodide transport for all mislocalizing mutations. However, SLC26A4 mutants are associated with variable thyroid dysfunction in affected subjects. The authors concluded that additional genetic and/or environmental factors influence the thyroid activity in Pendred syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The PDS gene has a relatively restricted pattern of expression, with PDS mRNA detected only in thyroid, inner ear, and kidney. <a href="#37" class="mim-tip-reference" title="Royaux, I. E., Wall, S. M., Karniski, L. P., Everett, L. A., Suzuki, K., Knepper, M. A., Green, E. D. <strong>Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion.</strong> Proc. Nat. Acad. Sci. 98: 4221-4226, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11274445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11274445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11274445[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.071516798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11274445">Royaux et al. (2001)</a> examined the distribution and function of pendrin in the mammalian kidney. Immunolocalization studies were performed using anti-pendrin polyclonal and monoclonal antibodies. Labeling was detected on the apical surface of a subpopulation of cells within the cortical collecting ducts (CCD) that also express H+-ATPase but not aquaporin-2 (<a href="/entry/107777">107777</a>), indicating that pendrin is present in intercalated cells of the CCD. Furthermore, pendrin was detected exclusively within the subpopulation of intercalated cells that express the H+-ATPase but not the anion exchanger 1 (AE1; <a href="/entry/109270">109270</a>) and that are thought to mediate bicarbonate secretion. The same distribution of pendrin was observed in mouse, rat, and human kidney. However, pendrin was not detected in kidneys from a Pds-knockout mouse. Perfused CCD tubules isolated from alkali-loaded wildtype mice secreted bicarbonate, whereas tubules from alkali-loaded Pds-knockout mice failed to secrete bicarbonate. Together, these studies indicated that pendrin is an apical anion transporter in intercalated cells of CCDs and has an essential role in renal bicarbonate secretion. Neither Pendred syndrome patients nor pendrin-deficient mice had been reported to develop overt acid-based disturbances, such as metabolic alkalosis. This may reflect the fact that the kidney has other means of regulating bicarbonate excretion in the absence of pendrin. Overt abnormalities in acid-base balance in pendrin-deficient humans or mice may be induced under conditions of extensive alkali loading or severe metabolic alkalosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11274445" 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 COS-7 cells and Chinese hamster ovary (CHO) cells transfected with expression vectors encoding SLC26A4 cDNA, and by comparison with studies using rat thyroid cells, <a href="#49" class="mim-tip-reference" title="Yoshida, A., Taniguchi, S., Hisatome, I., Royaux, I. E., Green, E. D., Kohn, L. D., Suzuki, K. <strong>Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells.</strong> J. Clin. Endocr. Metab. 87: 3356-3361, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12107249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12107249</a>] [<a href="https://doi.org/10.1210/jcem.87.7.8679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12107249">Yoshida et al. (2002)</a> showed that pendrin is an iodide-specific transporter in mammalian cells and is responsible for iodide efflux in the thyroid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12107249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Dentice, M., Luongo, C., Elefante, A., Ambrosio, R., Salzano, S., Zannini, M., Nitsch, R., Di Lauro, R., Rossi, G., Fenzi, G., Salvatore, D. <strong>Pendrin is a novel in vivo downstream target gene of the TTF-1/Nkx-2.1 homeodomain transcription factor in differentiated thyroid cells.</strong> Molec. Cell. Biol. 25: 10171-10182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16260629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16260629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16260629[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.25.22.10171-10182.2005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16260629">Dentice et al. (2005)</a> determined that Titf1 (<a href="/entry/600635">600635</a>) directly controls Slc26a4 expression in rat thyroid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16260629" 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 families with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#16" class="mim-tip-reference" title="Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D. <strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong> Nature Genet. 17: 411-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398842</a>] [<a href="https://doi.org/10.1038/ng1297-411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398842">Everett et al. (1997)</a> found 3 homozygous deleterious mutations in the SLC26A4 gene, each segregating with the disease in the respective families in which they occurred (e.g., <a href="#0001">605646.0001</a>). Implicating loss-of-function mutations in the PDS gene as a direct cause of thyroid disease in Pendred syndrome is relatively straightforward, as the gene is heavily expressed in thyroid, a tissue known to produce sulfated proteins. In particular, thyroglobulin (<a href="/entry/188450">188450</a>), the major secretory product of thyroid follicular cells, is sulfated both on tyrosine residues and asparagine-linked oligosaccharides. Sulfation of thyroglobulin is ubiquitous in organisms ranging from humans to lower eukaryotes, suggesting that this form of posttranslational modification serves an intrinsic role in thyroglobulin function. It had been suggested that thyroglobulin sulfation can influence subsequent iodination of the protein. The role of pendrin in cochlear development is less obvious. <a href="#16" class="mim-tip-reference" title="Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D. <strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong> Nature Genet. 17: 411-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398842</a>] [<a href="https://doi.org/10.1038/ng1297-411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398842">Everett et al. (1997)</a> speculated that Pendred syndrome may be more common than previously thought. They pointed out that another recessive locus for deafness, designated DFNB4 (<a href="/entry/600791">600791</a>), maps to 7q31, the same region as the PDS gene. They considered it likely that the DFNB4 individuals reported actually have Pendred syndrome, rather than mutations in another gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Van Hauwe, P., Everett, L. A., Coucke, P., Scott, D. A., Kraft, M. L., Ris-Stalpers, C., Bolder, C., Otten, B., de Vijlder, J. J. M., Dietrich, N. L., Ramesh, A., Srisailapathy, S. C. R., Parving, A., Cremers, C. W. R. J., Willems, P. J., Smith, R. J. H., Green, E. D., Van Camp, G. <strong>Two frequent missense mutations in Pendred syndrome.</strong> Hum. Molec. Genet. 7: 1099-1104, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618166</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618166">Van Hauwe et al. (1998)</a> performed mutation analysis of the PDS gene in 14 Pendred families originating from 7 countries and identified all mutations. The mutations included 3 single base deletions, 1 splice site mutation, and 10 missense mutations. One missense mutation (leu236 to pro; <a href="#0005">605646.0005</a>) was found in homozygous state in 2 consanguineous families and in heterozygous state in 5 additional nonconsanguineous families, thus being present in half the families. Another missense mutation (thr416 to pro; <a href="#0006">605646.0006</a>) was found in homozygous state in 1 family and in heterozygous state in 4 families. Pendred patients in 3 nonconsanguineous families were shown to be compound heterozygotes for these 2 frequent mutations. In total, 1 or both of these mutations were found in 9 of the 14 families analyzed. The findings should facilitate molecular diagnosis of Pendred syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Coyle, B., Reardon, W., Herbrick, J.-A., Tsui, L.-C., Gausden, E., Lee, J., Coffey, R., Grueters, A., Grossman, A., Phelps, P. D., Luxon, L., Kendall-Taylor, P., Scherer, S. W., Trembath, R. C. <strong>Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).</strong> Hum. Molec. Genet. 7: 1105-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618167</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618167">Coyle et al. (1998)</a> analyzed 56 kindreds, all with features suggestive of a diagnosis of Pendred syndrome. Molecular analysis of the PDS gene identified 47 of the 60 (78%) mutant alleles in 31 families; the families included 3 homozygous consanguineous kindreds and 1 extended family segregating 3 mutant alleles. Four recurrent mutations accounted for 35 (74%) of PDS disease chromosomes detected and haplotype analysis favored common founders rather than mutation hotspots within the PDS gene. A donor splice mutation (1001+1G-A; <a href="#0007">605646.0007</a>) was observed in 10 families, in 5 of which descendants could be traced to the northeast of England, the region in which the family described in 1896 by Pendred resided (<a href="#35" class="mim-tip-reference" title="Reardon, W., Coffey, R., Phelps, P. D., Luxon, L. M., Stephens, D., Kendall-Taylor, P., Britton, K. E., Grossman, A., Trembath, R. <strong>Pendred syndrome--100 years of underascertainment?</strong> Quart. J. Med. 90: 443-447, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302427</a>] [<a href="https://doi.org/10.1093/qjmed/90.7.443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302427">Reardon et al., 1997</a>). Analysis of parental DNA failed to reveal any de novo mutations in this study cohort, either within the familial or the isolated cases of Pendred syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9618167+9302427" 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 the index patient with PDS from a consanguineous kindred from northeastern Brazil, <a href="#23" class="mim-tip-reference" title="Kopp, P., Karamanoglu Arseven, O., Sabacan, L., Kotlar, T., Dupuis, J., Cavaliere, H., Santos, C. L. S., Jameson, J. L., Medeiros-Neto, G. <strong>Phenocopies for deafness and goiter development in a large inbred Brazilian kindred with Pendred's syndrome associated with a novel mutation in the PDS gene.</strong> J. Clin. Endocr. Metab. 84: 336-341, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9920104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9920104</a>] [<a href="https://doi.org/10.1210/jcem.84.1.5398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9920104">Kopp et al. (1999)</a> found homozygosity for a 279delT mutation (<a href="#0016">605646.0016</a>) in exon 3 of the PDS gene. The index patient showed the classic triad of deafness, positive perchlorate test, and goiter. Two other patients with deafness were homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wildtype allele. Surprisingly, 6 deaf individuals in this kindred were not homozygous for the 279delT mutation; 3 were heterozygous and 3 were homozygous for the wildtype allele, suggesting a probable distinct genetic cause for their deafness. The authors concluded from comparison of phenotypes and genotypes that phenocopies generated by distinct environmental and/or genetic causes were present in this kindred and that the diagnosis of PDS may be difficult without molecular analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a> identified 7 mutations in the PDS gene in 6 families with nonsyndromic congenital high frequency, fluctuating, sometimes progressive sensorineural hearing loss, and enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>) diagnosed by CT scan. PCR and direct sequencing of all 21 exons of PDS was undertaken. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The hearing loss that occurs in Pendred syndrome or in isolation as DFNB4 is associated with temporal bone abnormalities, ranging from isolated enlargement of the vestibular aqueduct (EVA) to Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2.5 turns is replaced by a hypoplastic coil of 1.5 turns. <a href="#8" class="mim-tip-reference" title="Campbell, C., Cucci, R. A., Prasad, S., Green, G. E., Edeal, J. B., Galer, C. E., Karniski, L. P., Sheffield, V. C., Smith, R. J. H. <strong>Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations.</strong> Hum. Mutat. 17: 403-411, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11317356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11317356</a>] [<a href="https://doi.org/10.1002/humu.1116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11317356">Campbell et al. (2001)</a> found mutations in 5 of 6 multiplex families with EVA (83%) and in 4 of 5 multiplex families with Mondini dysplasia (80%), implying that mutations in the SLC26A4 gene are the major genetic cause of these temporal abnormalities. In their analyses of Pendred syndrome and DFNB4, they found that the 2 most common mutations, T416P (<a href="#0006">605646.0006</a>) and IVS8+1G-A (<a href="#0007">605646.0007</a>), were present in 22% and 30% of families, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11317356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Rotman-Pikielny, P., Hirschberg, K., Maruvada, P., Suzuki, K., Royaux, I. E., Green, E. D., Kohn, L. D., Lippincott-Schwartz, J., Yen, P. M. <strong>Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome.</strong> Hum. Molec. Genet. 11: 2625-2633, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12354788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12354788</a>] [<a href="https://doi.org/10.1093/hmg/11.21.2625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12354788">Rotman-Pikielny et al. (2002)</a> studied the intracellular trafficking of fluorescently-tagged chimeras of wildtype pendrin and 3 common natural mutants (L236P, <a href="#0005">605646.0005</a>; T416P, <a href="#0006">605646.0006</a>; and G384E, <a href="/entry/606646#0008">606646.0008</a>) in living cells. Time-lapse imaging, dual color labeling, and fluorescent recovery after photobleaching studies demonstrated that GFP-wildtype pendrin targets to the plasma membrane. In contrast, all 3 mutant proteins were retained in the endoplasmic reticulum (ER) in colocalization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective, as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wildtype pendrin from targeting the plasma membrane. The authors suggested that ER retention and defective plasma membrane targeting of pendrin mutants may play a key role in the pathogenesis of Pendred syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12354788" 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="Park, H.-J., Shaukat, S., Liu, X.-Z., Hahn, S. H., Naz, S., Ghosh, M., Kim, H.-N., Moon, S.-K., Abe, S., Tukamoto, K., Riazuddin, S., Kabra, M., and 9 others. <strong>Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness.</strong> J. Med. Genet. 40: 242-248, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676893</a>] [<a href="https://doi.org/10.1136/jmg.40.4.242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676893">Park et al. (2003)</a> PCR amplified and sequenced 7 exons of SLC26A4 in 274 deaf probands from Korea, China, and Mongolia, and identified a total of 9 different mutations among 15 (5.5%) of the probands. Five of the mutations were novel and the other 4 had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with 3 or more affected offspring of consanguineous matings were analyzed for cosegregation of recessive deafness with short tandem repeat (STR) markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4-linked deafness. Eleven mutant alleles were identified in the 318 families, and all 11 were novel. SLC26A4-linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. <a href="#32" class="mim-tip-reference" title="Park, H.-J., Shaukat, S., Liu, X.-Z., Hahn, S. H., Naz, S., Ghosh, M., Kim, H.-N., Moon, S.-K., Abe, S., Tukamoto, K., Riazuddin, S., Kabra, M., and 9 others. <strong>Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness.</strong> J. Med. Genet. 40: 242-248, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676893</a>] [<a href="https://doi.org/10.1136/jmg.40.4.242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676893">Park et al. (2003)</a> concluded that approximately 5% of recessive deafness in south Asians and other populations results from mutation events at SLC26A4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12676893" 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 evaluate the contribution of the PDS gene (SLC26A4) in the genetic susceptibility of autoimmune thyroid disease (AITD; see <a href="/entry/608173">608173</a>), <a href="#19" class="mim-tip-reference" title="Hadj Kacem, H., Rebai, A., Kaffel, N., Masmoudi, S., Abid, M., Ayadi, H. <strong>PDS is a new susceptibility gene to autoimmune thyroid diseases: association and linkage study.</strong> J. Clin. Endocr. Metab. 88: 2274-2280, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12727986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12727986</a>] [<a href="https://doi.org/10.1210/jc.2002-021460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12727986">Hadj Kacem et al. (2003)</a> examined 4 microsatellite markers in the gene region. They genotyped 233 unrelated AITD patients, 15 multiplex AITD families, and 154 normal controls. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with Graves disease (GD; <a href="/entry/275000">275000</a>) and Hashimoto thyroiditis (HT; <a href="/entry/140300">140300</a>), respectively. The family-based association test showed significant association and linkage between AITDs and alleles 121 bp of D7S496 and 173 bp of D7S501. Results obtained by transmission disequilibrium test were in good agreement with those obtained by the family-based association test. Indeed, evidence for linkage and association of allele 121 bp of D7S496 with AITD was confirmed (P = 0.0114). The authors concluded that SLC26A4 should be considered a susceptibility gene to AITDs with varying contributions in each pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12727986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Albert, S., Blons, H., Jonard, L., Feldmann, D., Chauvin, P., Loundon, N., Sergent-Allaoui, A., Houang, M., Joannard, A., Schmerber, S., Delobel, B., Leman, J., and 18 others. <strong>SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations.</strong> Europ. J. Hum. Genet. 14: 773-779, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16570074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16570074</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16570074">Albert et al. (2006)</a> analyzed the SLC26A4 gene in 109 patients from 100 unrelated French Caucasian families with nonsyndromic deafness and enlarged vestibular aqueduct and no mutation in the GJB2 gene (<a href="/entry/121011">121011</a>). They identified 91 allelic variants in 40 unrelated families (prevalence of SLC26A4 mutations, 40%). <a href="#2" class="mim-tip-reference" title="Albert, S., Blons, H., Jonard, L., Feldmann, D., Chauvin, P., Loundon, N., Sergent-Allaoui, A., Houang, M., Joannard, A., Schmerber, S., Delobel, B., Leman, J., and 18 others. <strong>SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations.</strong> Europ. J. Hum. Genet. 14: 773-779, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16570074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16570074</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16570074">Albert et al. (2006)</a> estimated that up to 4% of nonsyndromic hearing impairment could be caused by SLC26A4 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16570074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Wang, Q.-J., Zhao, Y.-L., Rao, S.-Q., Guo, Y.-F., Yuan, H., Zong, L., Guan, J., Xu, B.-C., Wang, D.-Y., Han, M.-K., Lan, L., Zhai, S.-Q., Shen, Y. <strong>A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China.</strong> Clin. Genet. 72: 245-254, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17718863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17718863</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00862.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17718863">Wang et al. (2007)</a> identified 40 different SLC26A4 mutations, including 25 novel mutations, among 107 Chinese patients from 101 families with EVA. A splice site mutation (<a href="#0029">605646.0029</a>) in intron 7 was the most common mutation, accounting for 57.6% of the mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17718863" 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>Among 105 Spanish patients from 47 families with Pendred syndrome or nonsyndromic EVA and 20 families with recessive nonsyndromic hearing loss that segregated with the DFNB4 locus, <a href="#33" class="mim-tip-reference" title="Pera, A., Villamar, M., Vinuela, A., Gandia, M., Meda, C., Moreno, F., Hernandez-Chico, C. <strong>A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.</strong> Europ. J. Hum. Genet. 16: 888-896, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285825</a>] [<a href="https://doi.org/10.1038/ejhg.2008.30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285825">Pera et al. (2008)</a> identified 24 different mutations in the SLC26A4 gene, including 8 novel mutations. The Q514K variant (<a href="#0030">605646.0030</a>) was the most prevalent mutation, accounting for 6 (17%) of 36 mutated alleles identified in this study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285825" 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="#48" class="mim-tip-reference" title="Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G. <strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong> J. Med. Genet. 45: 411-419, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>] [<a href="https://doi.org/10.1136/jmg.2007.054635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18310264">Yoon et al. (2008)</a> performed in vitro cellular expression studies of 11 different SLC26A4 mutations (see, e.g., <a href="#0004">605646.0004</a>-<a href="/entry/605656#0006">605656.0006</a>; <a href="#0008">605646.0008</a>; <a href="#0011">605646.0011</a>). Most of the mutations caused retention of the gene product in the intracellular region, whereas wildtype pendrin reached the plasma membrane. However, each mutant protein exhibited a different cellular localization, a different degree of N-glycosylation, and a different degree of sensitivity to rescue treatments. The H723R mutant (<a href="#0011">605646.0011</a>) was expressed mostly in endoplasmic reticulum, and the defects could be restored somewhat by low temperature incubation. In contrast, the L236P mutant was found mainly in the centrosomal region and was temperature insensitive. <a href="#48" class="mim-tip-reference" title="Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G. <strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong> J. Med. Genet. 45: 411-419, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>] [<a href="https://doi.org/10.1136/jmg.2007.054635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18310264">Yoon et al. (2008)</a> concluded that mutant-specific methods would be required to rescue the conformational defects of each folding mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18310264" 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="Anwar, S., Riazuddin, S., Ahmed, Z. M., Tasneem, S., Jaleel, A., Khan, S. Y., Griffith, A. J., Friedman, T. B., Riazuddin, S. <strong>SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis.</strong> J. Hum. Genet. 54: 266-270, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19287372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19287372</a>] [<a href="https://doi.org/10.1038/jhg.2009.21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19287372">Anwar et al. (2009)</a> analyzed the SLC26A4 gene in 46 consanguineous Pakistani families cosegregating deafness with STR markers linked to SLC26A4 and identified 16 probable pathogenic variants. Combined with earlier reported data (see <a href="#32" class="mim-tip-reference" title="Park, H.-J., Shaukat, S., Liu, X.-Z., Hahn, S. H., Naz, S., Ghosh, M., Kim, H.-N., Moon, S.-K., Abe, S., Tukamoto, K., Riazuddin, S., Kabra, M., and 9 others. <strong>Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness.</strong> J. Med. Genet. 40: 242-248, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676893</a>] [<a href="https://doi.org/10.1136/jmg.40.4.242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676893">Park et al., 2003</a>), SLC26A4 mutations were identified in 56 (7.2%) of 775 Pakistani families cosegregating recessive severe to profound deafness with or without goiter, making SLC26A4 mutations the most common known cause of genetic deafness in this population. Six of the pathogenic variants were found in more than 1 family, and haplotype analysis suggested that they are founder mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12676893+19287372" 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 3 unrelated patients with semicircular canal dehiscence and no family history of the disorder or of deafness, <a href="#12" class="mim-tip-reference" title="Crovetto, M. A., Whyte, J., Sarasola, E., Rodriguez, J. A., Garcia-Barcina, M. J. <strong>Absence of COCH gene mutations in patients with superior semicircular canal dehiscence. (Letter)</strong> Am. J. Med. Genet. 158A: 251-253, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22139968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22139968</a>] [<a href="https://doi.org/10.1002/ajmg.a.34377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22139968">Crovetto et al. (2012)</a> excluded the 3 most common mutations in the SLC26A4 gene (<a href="#0005">605646.0005</a>, <a href="#0006">605646.0006</a>, and <a href="#0007">605646.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22139968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Chattaraj, P., Munjal, T., Honda, K., Rendtorff, N. D., Ratay, J. S., Muskett, J. A., Risso, D. S., Roux, I., Gertz, E. M., Schaffer, A. A., Friedman, T. B., Morell, R. J., Tranebjaerg, L., Griffith, A. J. <strong>A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct.</strong> J. Med. Genet. 54: 665-673, 2017. Note: Erratum: J. Med. Genet. 55: 846 only, 2018. Erratum: J. Med. Genet. 6July, 2023. Advance Electronic Publication.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28780564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28780564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28780564[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/10.1136/jmedgenet-2017-104721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28780564">Chattaraj et al. (2017)</a> performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 gene in patients with EVA (<a href="/entry/600791">600791</a>) and only 1 detected mutant allele in the SLC26A4 gene. The authors identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on 7 of 10 mutation-negative chromosomes in a National Institutes of Health discovery cohort and 6 of 6 mutation-negative chromosomes in a Danish replication cohort was higher than the observed prevalence of 28 of 1,006 Caucasian control chromosomes (p less than 0.0001 for each EVA cohort). The corresponding heterozygous carrier rate was 28 of 503 (5.6%). The prevalence of CEVA (11 of 126) was also increased among EVA chromosomes with no mutations detected (p = 0.0042). <a href="#9" class="mim-tip-reference" title="Chattaraj, P., Munjal, T., Honda, K., Rendtorff, N. D., Ratay, J. S., Muskett, J. A., Risso, D. S., Roux, I., Gertz, E. M., Schaffer, A. A., Friedman, T. B., Morell, R. J., Tranebjaerg, L., Griffith, A. J. <strong>A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct.</strong> J. Med. Genet. 54: 665-673, 2017. Note: Erratum: J. Med. Genet. 55: 846 only, 2018. Erratum: J. Med. Genet. 6July, 2023. Advance Electronic Publication.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28780564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28780564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28780564[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/10.1136/jmedgenet-2017-104721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28780564">Chattaraj et al. (2017)</a> concluded that the CEVA haplotype causally contributes to most cases of Caucasian EVA, being present in cases where only 1 mutation is detected by traditional exonic sequencing, and possibly in some cases where no mutation has been detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28780564" 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="#42" class="mim-tip-reference" title="Tsukamoto, K., Suzuki, H., Harada, D., Namba, A., Abe, S., Usami, S. <strong>Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese.</strong> Europ. J. Hum. Genet. 11: 916-922, 2003. Note: Erratum: Europ. J. Hum. Genet. 12: 422 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14508505</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14508505">Tsukamoto et al. (2003)</a> screened 10 Japanese families with Pendred syndrome, 32 Japanese families with bilateral sensorineural hearing loss associated with enlarged vestibular aqueduct, and 96 unrelated Japanese controls for mutations in the SLC26A4 gene. They identified causative mutations in 90% of the typical Pendred syndrome families and in 78.1% of those with sensorineural hearing loss with EVA. The same combination of mutations resulted in variable phenotypic expression (see, e.g., <a href="#0011">605646.0011</a>), suggesting that the 2 conditions are part of a continuous spectrum of disease. <a href="#42" class="mim-tip-reference" title="Tsukamoto, K., Suzuki, H., Harada, D., Namba, A., Abe, S., Usami, S. <strong>Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese.</strong> Europ. J. Hum. Genet. 11: 916-922, 2003. Note: Erratum: Europ. J. Hum. Genet. 12: 422 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14508505</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14508505">Tsukamoto et al. (2003)</a> commented that the 3 frequent mutations accounting for nearly half of all SLC26A4 mutations in Caucasians (L236P, <a href="#0005">605646.0005</a>; T416P, <a href="#0006">605646.0006</a>; and IVS8+1G-A, <a href="#0007">605646.0007</a>) are rare in Japanese. The H723R mutation (<a href="#0011">605646.0011</a>) accounted for over half of the mutations in their study, suggesting a possible founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14508505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Pryor, S. P., Madeo, A. C., Reynolds, J. C., Sarlis, N. J., Arnos, K. S., Nance, W. E., Yang, Y., Zalewski, C. K., Brewer, C. C., Butman, J. A., Griffith, A. J. <strong>SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. (Letter)</strong> J. Med. Genet. 42: 159-165, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689455</a>] [<a href="https://doi.org/10.1136/jmg.2004.024208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689455">Pryor et al. (2005)</a> evaluated the clinical phenotype and SLC26A4 genotype of 39 patients with EVA from 31 families, definitively classifying 29 individuals. All 11 PDS patients had 2 mutant SLC26A4 alleles, whereas all 18 nonsyndromic EVA patients had either 1 or no SLC26A4 mutant alleles. <a href="#34" class="mim-tip-reference" title="Pryor, S. P., Madeo, A. C., Reynolds, J. C., Sarlis, N. J., Arnos, K. S., Nance, W. E., Yang, Y., Zalewski, C. K., Brewer, C. C., Butman, J. A., Griffith, A. J. <strong>SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. (Letter)</strong> J. Med. Genet. 42: 159-165, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689455</a>] [<a href="https://doi.org/10.1136/jmg.2004.024208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689455">Pryor et al. (2005)</a> concluded that PDS and nonsyndromic EVA are distinct clinical and genetic entities, with PDS being a genetically homogeneous disorder caused by biallelic SLC26A4 mutations, and at least some cases of nonsyndromic EVA being associated with a single SLC26A4 mutation. They noted that the detection of a single mutant SLC26A4 allele is incompletely diagnostic without additional clinical evaluation to differentiate PDS from nonsyndromic EVA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689455" 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="Napiontek, U., Borck, G., Muller-Forell, W., Pfarr, N., Bohnert, A., Keilmann, A., Pohlenz, J. <strong>Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene.</strong> J. Clin. Endocr. Metab. 89: 5347-5351, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531480</a>] [<a href="https://doi.org/10.1210/jc.2004-1013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531480">Napiontek et al. (2004)</a> performed a detailed clinical and genetic study in 3 adult German sibs with typical PDS caused by the common homozygous SLC26A4 mutation T416P (<a href="#0006">605646.0006</a>). Long-term audiologic follow-up of 23 to 25 years showed that T416P associated with a distinct type of hearing loss in each of the 3 sibs: moderate to profound progressive deafness, profound nonprogressive deafness, and a milder but more rapidly progressing deafness. <a href="#29" class="mim-tip-reference" title="Napiontek, U., Borck, G., Muller-Forell, W., Pfarr, N., Bohnert, A., Keilmann, A., Pohlenz, J. <strong>Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene.</strong> J. Clin. Endocr. Metab. 89: 5347-5351, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531480</a>] [<a href="https://doi.org/10.1210/jc.2004-1013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531480">Napiontek et al. (2004)</a> concluded that these phenotypic differences were not caused by either different degrees of inner-ear malformation or sequence variations in the GJB2 gene (<a href="/entry/121011">121011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531480" 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>Although recessive mutations in SLC26A4 are known to be responsible for Pendred syndrome or nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA; <a href="/entry/600791">600791</a>), a large percentage of patients with these phenotype lack mutations in the SLC26A4 coding region in one or both alleles. <a href="#47" class="mim-tip-reference" title="Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. <strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong> Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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/10.1086/518314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503324">Yang et al. (2007)</a> identified and characterized a key transcriptional regulatory element in the 5-prime UTR of the SLC26A4 gene that binds FOXI1 (<a href="/entry/601093">601093</a>), a transcriptional activator of SLC26A4. In 9 patients with Pendred syndrome or nonsyndromic EVA, a novel -103T-C mutation (<a href="#0027">605646.0027</a>) in this regulatory element interfered with FOXI1 binding and completely abolished FOXI1-mediated transcriptional activation. <a href="#47" class="mim-tip-reference" title="Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. <strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong> Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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/10.1086/518314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503324">Yang et al. (2007)</a> also identified 2 Pendred and 4 EVA patients with mutations in FOXI1 that compromised its ability to activate SLC26A4 transcription; 1 of the latter EVA patients was a double heterozygote who also carried a heterozygous mutation in the SLC26A4 gene (see <a href="#0028">605646.0028</a> and <a href="/entry/601093#0001">601093.0001</a>). This finding was consistent with their observation that EVA occurs in the mouse mutant doubly heterozygous for mutations in these 2 genes (<a href="#22" class="mim-tip-reference" title="Hulander, M., Kiernan, A. E., Blomqvist, S. R., Carlsson, P., Samuelsson, E. J., Johansson, B. R., Steel, K. P., Enerback, S. <strong>Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice.</strong> Development 130: 2013-2025, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12642503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12642503</a>] [<a href="https://doi.org/10.1242/dev.00376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12642503">Hulander et al., 2003</a>), and the results supported a dosage-dependent model for the molecular pathogenesis of Pendred syndrome and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery. <a href="#47" class="mim-tip-reference" title="Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. <strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong> Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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/10.1086/518314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503324">Yang et al. (2007)</a> stated the this was the first example of digenic inheritance to be verified as a cause of human deafness. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17503324+12642503" 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="Azaiez, H., Yang, T., Prasad, S., Sorensen, J. L., Nishimura, C. J., Kimberling, W. J., Smith, R. J. H. <strong>Genotype-phenotype correlations for SLC26A4-related deafness.</strong> Hum. Genet. 122: 451-457, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17690912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17690912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17690912[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/10.1007/s00439-007-0415-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17690912">Azaiez et al. (2007)</a> analyzed the SLC26A4 gene in 474 patients with sensorineural hearing loss and abnormalities of the inner ear demonstrated on CT scan of the temporal bone. They detected 2 mutations in 16% of patients, 1 mutation in 19% of patients, and no mutation in 65% of patients. Comparing the distribution of SLC26A4 mutations across phenotypes, the authors found a statistically significant difference between Pendred syndrome patients and nonsyndromic EVA patients (p = 0.005) and between patients with EVA versus Mondini malformation (p = 0.0003). Pendred syndrome patients had the most severe phenotype and the most homogeneous etiology, whereas EVA patients had the least severe phenotype and the most heterogeneous etiology. For all patients, variability in the degree of hearing loss was seen across genotypes, implicating other genetic and/or environmental factors in the pathogenesis of the Pendred syndrome/Mondini/EVA disease spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17690912" 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="#15" class="mim-tip-reference" title="Everett, L. A., Belyantseva, I. A., Noben-Trauth, K., Cantos, R., Chen, A., Thakkar, S. I., Hoogstraten-Miller, S. L., Kachar, B., Wu, D. K., Green, E. D. <strong>Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome.</strong> Hum. Molec. Genet. 10: 153-161, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11152663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11152663</a>] [<a href="https://doi.org/10.1093/hmg/10.2.153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11152663">Everett et al. (2001)</a> generated a Pds knockout mouse. Pds -/- mice are completely deaf and also display signs of vestibular dysfunction. The inner ears appear to develop normally until embryonic day 15, after which time severe endolymphatic dilatation occurs, reminiscent of that seen radiologically in deaf individuals with PDS mutations. Additionally, in the second postnatal week severe degeneration of sensory cells and malformation of otoconia and otoconial membranes occur, as revealed by scanning electron and fluorescence confocal microscopy. No thyroid abnormality was noted in this particular mouse strain (in a 129Sv/Ev background). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11152663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Dror, A. A., Politi, Y., Shahin, H., Lenz, D. R., Dossena, S., Nofziger, C., Fuchs, H., Hrabe de Angelis, M., Paulmichl, M., Weiner, S., Avraham, K. B. <strong>Calcium oxalate stone formation in the inner ear as a result of an Slc26a4 mutation.</strong> J. Biol. Chem. 285: 21724-21735, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20442411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20442411</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20442411[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M110.120188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20442411">Dror et al. (2010)</a> identified a recessive mouse mutant termed 'loop' that is caused by a homozygous ser408-to-phe (S408F) substitution in a hydrophobic signature within the ninth transmembrane domain of Slc26a4. Loop/loop mice were profoundly deaf and showed abnormal vestibular behavior, such as unsteady gait, circling, absence of reaching response, and tilted body. In vitro functional expression studies in HEK293 cells showed that the S408F-mutant protein had compromised anion exchange activity, particularly of anion efflux. Detailed examination of the mutant mouse inner ear showed dramatic changes in mineral composition and size in the utricle and saccule in a differential manner. The utricles of 2-month-old wildtype mice showed thousands of small calcitic otoconia, whereas loop/loop mice had 1 giant calcitic stone. In the saccule, abnormal large stones composed of calcium oxalate formed. The differential abnormal mineralization processes between the utricle and saccule resulted from different calcium concentrations in these chambers due to different pH levels. For example, the utricle is exposed to endolymph, whereas the saccule is not. Loop/loop mice also showed deposition of ectopic stones in other components of the vestibular system. Overall, the aberrant mineralization process in mutant mice resulted in the formation of giant minerals that could no longer serve their role in proper hair cell stimulation and vestibular function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20442411" 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=605646[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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<p>In a family with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#16" class="mim-tip-reference" title="Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D. <strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong> Nature Genet. 17: 411-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398842</a>] [<a href="https://doi.org/10.1038/ng1297-411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398842">Everett et al. (1997)</a> demonstrated that affected members had a homozygous T-to-G transversion in the SLC26A4 gene, predicted to cause a phe667-to-cys (F667C) amino acid substitution near the C terminus of the pendrin protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398842" 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> rs397516417 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516417;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/rs397516417?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=rs397516417" 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=rs397516417" 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=RCV000036439 OR RCV000454189 OR RCV001807761 OR RCV001852760" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036439, RCV000454189, RCV001807761, RCV001852760" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036439...</a>
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<p>In a family with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#16" class="mim-tip-reference" title="Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D. <strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong> Nature Genet. 17: 411-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398842</a>] [<a href="https://doi.org/10.1038/ng1297-411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398842">Everett et al. (1997)</a> demonstrated that affected members had a homozygous deletion of a single G at position 1565 (1565delG) of the SLC26A4 gene, which was predicted to result either in a frameshift and premature termination of the pendrin protein or in aberrant splicing of the mRNA, or both. The deleted G is either part of or immediately adjacent to a splice donor site; thus, the precise effect of the mutation could not be predicted with certainty. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398842" 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">rs397516413 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516413;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=rs397516413" 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=rs397516413" 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=RCV000036426 OR RCV000169097 OR RCV000225034 OR RCV000802527 OR RCV001291249 OR RCV002496558" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036426, RCV000169097, RCV000225034, RCV000802527, RCV001291249, RCV002496558" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036426...</a>
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<p>In 3 families with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#16" class="mim-tip-reference" title="Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D. <strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong> Nature Genet. 17: 411-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398842</a>] [<a href="https://doi.org/10.1038/ng1297-411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398842">Everett et al. (1997)</a> found a homozygous deletion of a single T at position 1421 of the SLC26A4 gene, which was predicted to result in a frameshift and premature termination of the pendrin protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398842" 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>.0004 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
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SLC26A4, GLY497SER AND ILE490LEU
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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> rs111033308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033308;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/rs111033308?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=rs111033308" 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=rs111033308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs200511789 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200511789;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/rs200511789?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=rs200511789" 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=rs200511789" 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=RCV000005085 OR RCV000036444 OR RCV000154348 OR RCV000169242 OR RCV000489866 OR RCV000673746 OR RCV000938882 OR RCV001004645 OR RCV001162717 OR RCV001375472 OR RCV004798754" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005085, RCV000036444, RCV000154348, RCV000169242, RCV000489866, RCV000673746, RCV000938882, RCV001004645, RCV001162717, RCV001375472, RCV004798754" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005085...</a>
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<p>In affected members of a large consanguineous Indian family with nonsyndromic autosomal recessive deafness-4 and enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>) mapping to 7q31, <a href="#25" class="mim-tip-reference" title="Li, X. C., Everett, L. A., Lalwani, A. K., Desmukh, D., Friedman, T. B., Green, E. D., Wilcox, E. R. <strong>A mutation in PDS causes non-syndromic recessive deafness. (Letter)</strong> Nature Genet. 18: 215-217, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9500541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9500541</a>] [<a href="https://doi.org/10.1038/ng0398-215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9500541">Li et al. (1998)</a> identified homozygosity for 2 single-base changes in exon 13 of the SLC26A4 gene. The first was a 1713G-to-A transition, resulting in a predicted gly497-to-ser (G497S) substitution, and the second was a 1692A-to-C transversion, resulting in a predicted ile490-to-leu (I490L) substitution. The unaffected parents in all cases were heterozygous for both mutations. Both of the changes occurred within the last predicted transmembrane domain of the pendrin protein. Gly497 is 1 of only 16 strictly conserved amino acids in the entire sequence of all 15 of the closest-related sulfate transporter proteins. The G497S substitution would introduce a polar constraint inside the transmembrane domain and likely alter the conformation of protein, whereas the functional significance of the I490L substitution, if any, was less obvious. It appeared to be found only in conjunction with the G497S substitution, as neither change was detected in 184 random normal chromosomes from the same geographic area. The authors suggested that the I490L substitution may create a subtle alteration in the protein. Ten individuals ranging in age from 5 to 38 years were affected. No goiter was palpable in any of the affected individuals, and, although the perchlorate discharge test was not available, several other tests of thyroid function were normal. Axial and coronal computerized tomography of the temporal bone showed no Mondini-type cochlear malformation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9500541" 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 in vitro cellular expression studies, <a href="#48" class="mim-tip-reference" title="Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G. <strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong> J. Med. Genet. 45: 411-419, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>] [<a href="https://doi.org/10.1136/jmg.2007.054635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18310264">Yoon et al. (2008)</a> demonstrated that the G497S mutant protein was retained in the intracellular region, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18310264" 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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SLC26A4, LEU236PRO
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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> rs80338848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338848;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/rs80338848?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=rs80338848" 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=rs80338848" 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=RCV000005086 OR RCV000036505 OR RCV000524013 OR RCV000824766 OR RCV001089560 OR RCV001375179 OR RCV004528073" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005086, RCV000036505, RCV000524013, RCV000824766, RCV001089560, RCV001375179, RCV004528073" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005086...</a>
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<p>Both <a href="#44" class="mim-tip-reference" title="Van Hauwe, P., Everett, L. A., Coucke, P., Scott, D. A., Kraft, M. L., Ris-Stalpers, C., Bolder, C., Otten, B., de Vijlder, J. J. M., Dietrich, N. L., Ramesh, A., Srisailapathy, S. C. R., Parving, A., Cremers, C. W. R. J., Willems, P. J., Smith, R. J. H., Green, E. D., Van Camp, G. <strong>Two frequent missense mutations in Pendred syndrome.</strong> Hum. Molec. Genet. 7: 1099-1104, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618166</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618166">Van Hauwe et al. (1998)</a> and <a href="#11" class="mim-tip-reference" title="Coyle, B., Reardon, W., Herbrick, J.-A., Tsui, L.-C., Gausden, E., Lee, J., Coffey, R., Grueters, A., Grossman, A., Phelps, P. D., Luxon, L., Kendall-Taylor, P., Scherer, S. W., Trembath, R. C. <strong>Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).</strong> Hum. Molec. Genet. 7: 1105-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618167</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618167">Coyle et al. (1998)</a> found a leu236-to-pro mutation (L236P) to be a frequent basis of Pendred syndrome (PDS; <a href="/entry/274600">274600</a>). The amino acid substitution results from a T-to-C transition at nucleotide 707 of the SLC26A4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9618166+9618167" 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 in vitro cellular expression studies, <a href="#48" class="mim-tip-reference" title="Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G. <strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong> J. Med. Genet. 45: 411-419, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>] [<a href="https://doi.org/10.1136/jmg.2007.054635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18310264">Yoon et al. (2008)</a> demonstrated that the L236P mutant protein was initially found in the endoplasmic reticulum, but later was highly concentrated at the centrosome, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity, and the defect was not corrected by lower temperature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18310264" 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> rs28939086 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28939086;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/rs28939086?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=rs28939086" 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=rs28939086" 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=RCV000005087 OR RCV000036432 OR RCV000435157 OR RCV000824771 OR RCV001004638 OR RCV004528074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005087, RCV000036432, RCV000435157, RCV000824771, RCV001004638, RCV004528074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005087...</a>
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<p>Both <a href="#44" class="mim-tip-reference" title="Van Hauwe, P., Everett, L. A., Coucke, P., Scott, D. A., Kraft, M. L., Ris-Stalpers, C., Bolder, C., Otten, B., de Vijlder, J. J. M., Dietrich, N. L., Ramesh, A., Srisailapathy, S. C. R., Parving, A., Cremers, C. W. R. J., Willems, P. J., Smith, R. J. H., Green, E. D., Van Camp, G. <strong>Two frequent missense mutations in Pendred syndrome.</strong> Hum. Molec. Genet. 7: 1099-1104, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618166</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618166">Van Hauwe et al. (1998)</a> and <a href="#11" class="mim-tip-reference" title="Coyle, B., Reardon, W., Herbrick, J.-A., Tsui, L.-C., Gausden, E., Lee, J., Coffey, R., Grueters, A., Grossman, A., Phelps, P. D., Luxon, L., Kendall-Taylor, P., Scherer, S. W., Trembath, R. C. <strong>Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).</strong> Hum. Molec. Genet. 7: 1105-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618167</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618167">Coyle et al. (1998)</a> found that a thr416-to-pro (T416P) amino acid substitution resulting from a 1246A-C transversion in the SLC26A4 gene was a frequent finding in cases of Pendred syndrome (PDS; <a href="/entry/274600">274600</a>). <a href="#44" class="mim-tip-reference" title="Van Hauwe, P., Everett, L. A., Coucke, P., Scott, D. A., Kraft, M. L., Ris-Stalpers, C., Bolder, C., Otten, B., de Vijlder, J. J. M., Dietrich, N. L., Ramesh, A., Srisailapathy, S. C. R., Parving, A., Cremers, C. W. R. J., Willems, P. J., Smith, R. J. H., Green, E. D., Van Camp, G. <strong>Two frequent missense mutations in Pendred syndrome.</strong> Hum. Molec. Genet. 7: 1099-1104, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618166</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618166">Van Hauwe et al. (1998)</a> found 1 or both of the L236P (<a href="#0005">605646.0005</a>) and T416P mutations in 9 of 14 families studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9618166+9618167" 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 3 adult German sibs with PDS and each homozygous for the T416P mutation, <a href="#29" class="mim-tip-reference" title="Napiontek, U., Borck, G., Muller-Forell, W., Pfarr, N., Bohnert, A., Keilmann, A., Pohlenz, J. <strong>Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene.</strong> J. Clin. Endocr. Metab. 89: 5347-5351, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531480</a>] [<a href="https://doi.org/10.1210/jc.2004-1013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15531480">Napiontek et al. (2004)</a> noted a distinct type of hearing loss in each sib. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531480" 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 in vitro cellular expression studies, <a href="#48" class="mim-tip-reference" title="Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G. <strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong> J. Med. Genet. 45: 411-419, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>] [<a href="https://doi.org/10.1136/jmg.2007.054635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18310264">Yoon et al. (2008)</a> demonstrated that the T416P mutant protein was retained in the intracellular region, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18310264" 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> rs80338849 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338849;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/rs80338849?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=rs80338849" 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=rs80338849" 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=RCV000005088 OR RCV000036418 OR RCV000239276 OR RCV000477914 OR RCV000824768 OR RCV004528075" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005088, RCV000036418, RCV000239276, RCV000477914, RCV000824768, RCV004528075" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005088...</a>
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<p><a href="#11" class="mim-tip-reference" title="Coyle, B., Reardon, W., Herbrick, J.-A., Tsui, L.-C., Gausden, E., Lee, J., Coffey, R., Grueters, A., Grossman, A., Phelps, P. D., Luxon, L., Kendall-Taylor, P., Scherer, S. W., Trembath, R. C. <strong>Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).</strong> Hum. Molec. Genet. 7: 1105-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618167</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618167">Coyle et al. (1998)</a> found that a 1001+1G-A donor splice site mutation in the SLC26A4 gene was a recurrent finding in cases of Pendred syndrome (PDS; <a href="/entry/274600">274600</a>). This and the L236P (<a href="#0005">605646.0005</a>), T416P (<a href="#0006">605646.0006</a>), and glu384-to-gly (E384G; <a href="#0008">605646.0008</a>) mutations accounted for 35 (74%) of PDS disease chromosomes detected by <a href="#11" class="mim-tip-reference" title="Coyle, B., Reardon, W., Herbrick, J.-A., Tsui, L.-C., Gausden, E., Lee, J., Coffey, R., Grueters, A., Grossman, A., Phelps, P. D., Luxon, L., Kendall-Taylor, P., Scherer, S. W., Trembath, R. C. <strong>Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).</strong> Hum. Molec. Genet. 7: 1105-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618167</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618167">Coyle et al. (1998)</a> and haplotype analysis favored common founders rather than mutation hotspots within the SLC26A4 gene. This donor splice site mutation was observed in 10 British families, in 5 of which descendants could be traced to the northeast of England, the region in which the family described in 1896 by Pendred resided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618167" 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> rs111033244 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033244;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/rs111033244?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=rs111033244" 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=rs111033244" 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=RCV000005089 OR RCV000036425 OR RCV000520205 OR RCV001095693 OR RCV002482829 OR RCV004528076" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005089, RCV000036425, RCV000520205, RCV001095693, RCV002482829, RCV004528076" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005089...</a>
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<p>In patients with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#11" class="mim-tip-reference" title="Coyle, B., Reardon, W., Herbrick, J.-A., Tsui, L.-C., Gausden, E., Lee, J., Coffey, R., Grueters, A., Grossman, A., Phelps, P. D., Luxon, L., Kendall-Taylor, P., Scherer, S. W., Trembath, R. C. <strong>Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).</strong> Hum. Molec. Genet. 7: 1105-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618167</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618167">Coyle et al. (1998)</a> identified an A-to-G change at nucleotide 1151 that resulted in a glu384-to-gly (E384G) substitution in the SLC26A4 gene. See <a href="#0007">605646.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618167" 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 in vitro cellular expression studies, <a href="#48" class="mim-tip-reference" title="Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G. <strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong> J. Med. Genet. 45: 411-419, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>] [<a href="https://doi.org/10.1136/jmg.2007.054635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18310264">Yoon et al. (2008)</a> demonstrated that the E384G mutant protein was retained in the intracellular region, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18310264" 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>.0009 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs111033303 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033303;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/rs111033303?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=rs111033303" 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=rs111033303" 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=RCV000005090 OR RCV000036501 OR RCV000308471 OR RCV000344627 OR RCV000824764 OR RCV004528077" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005090, RCV000036501, RCV000308471, RCV000344627, RCV000824764, RCV004528077" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005090...</a>
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<p>In 1 family with autosomal recessive deafness-4 and enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>) that did not fulfill the traditional criteria for Pendred syndrome (<a href="/entry/274600">274600</a>), <a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a> found that 2 affected sons were homozygous for a G-to-T transversion at nucleotide 626 of the SLC26A4 gene, leading to a gly-to-val substitution at codon 209 (G209V) in the conserved region of exon 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" 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">rs121908361 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908361;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=rs121908361" 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=rs121908361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>), <a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a> identified an A-to-G transition at nucleotide 1105 of the SLC26A4 gene leading to a lys-to-glu substitution in codon 369 (K369E). The patient was compound heterozygous for the his723-to-arg mutation (H723R; <a href="#0011">605646.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" 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 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908362 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908362;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/rs121908362?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=rs121908362" 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=rs121908362" 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=RCV000005094 OR RCV000005095 OR RCV000036477 OR RCV000480319 OR RCV001293683 OR RCV002476929 OR RCV004528078" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005094, RCV000005095, RCV000036477, RCV000480319, RCV001293683, RCV002476929, RCV004528078" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005094...</a>
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<p>In 3 families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>), <a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a> identified a 2168A-G transition in exon 19 of the SLC26A4 gene, causing a his723-to-arg (H723R) substitution. This mutation was found in homozygosity in 1 family and in compound heterozygosity in affected members of the other 2 families, who also carried a 2162C-T transition in exon 19 of the SLC26A4 gene, resulting in a thr721-to-met (T721M; <a href="#0012">605646.0012</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Tekin, M., Akcayoz, D., Comak, E., Bogoclu, G., Duman, T., Fitoz, S., Ilhan, I., Akar, N. <strong>Screening the SLC26A4 gene in probands with deafness and goiter (Pendred syndrome) ascertained from a large group of students of the schools for the deaf in Turkey. (Letter)</strong> Clin. Genet. 64: 371-374, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12974744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12974744</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00144.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12974744">Tekin et al. (2003)</a> identified the H723R mutation in homozygous state in a Turkish patient with classic Pendred syndrome (PDS; <a href="/entry/274600">274600</a>). They noted that the mutation had been identified in families from Japan and China in which affected members had sensorineural hearing loss and enlarged vestibular aqueduct without goiter. <a href="#41" class="mim-tip-reference" title="Tekin, M., Akcayoz, D., Comak, E., Bogoclu, G., Duman, T., Fitoz, S., Ilhan, I., Akar, N. <strong>Screening the SLC26A4 gene in probands with deafness and goiter (Pendred syndrome) ascertained from a large group of students of the schools for the deaf in Turkey. (Letter)</strong> Clin. Genet. 64: 371-374, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12974744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12974744</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00144.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12974744">Tekin et al. (2003)</a> suggested that the detection of the H723R mutation in Turkey reflected the migration of the Turkish people from central Asia more than 1,000 years ago. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12974744" 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 2 sibs with enlarged vestibular aqueduct and an unrelated patient with Pendred syndrome, <a href="#42" class="mim-tip-reference" title="Tsukamoto, K., Suzuki, H., Harada, D., Namba, A., Abe, S., Usami, S. <strong>Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese.</strong> Europ. J. Hum. Genet. 11: 916-922, 2003. Note: Erratum: Europ. J. Hum. Genet. 12: 422 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14508505</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14508505">Tsukamoto et al. (2003)</a> identified compound heterozygosity for the H723R and T721M mutations in the SLC26A4 gene, and concluded that the 2 conditions are part of a continuous spectrum of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14508505" 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>Among 26 Korean patients with DFNB4 with enlarged vestibular aqueduct (EVA), <a href="#31" class="mim-tip-reference" title="Park, H.-J., Lee, S.-J., Jin, H.-S., Lee, J. O., Go, S.-H., Jang, H. S., Moon, S.-K., Lee, S.-C., Chun, Y.-M., Lee, H.-K., Choi, J.-Y., Jung, S.-C., Griffith, A. J., Koo, S. K. <strong>Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans.</strong> Clin. Genet. 67: 160-165, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15679828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15679828</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00386.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15679828">Park et al. (2005)</a> found that the H723R mutation was the most common, accounting for 40% of the mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15679828" 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>Among Chinese patients with DFNB4 with EVA, <a href="#45" class="mim-tip-reference" title="Wang, Q.-J., Zhao, Y.-L., Rao, S.-Q., Guo, Y.-F., Yuan, H., Zong, L., Guan, J., Xu, B.-C., Wang, D.-Y., Han, M.-K., Lan, L., Zhai, S.-Q., Shen, Y. <strong>A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China.</strong> Clin. Genet. 72: 245-254, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17718863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17718863</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00862.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17718863">Wang et al. (2007)</a> found that H723R was the second most common mutation, accounting for 9% of mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17718863" 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 in vitro cellular expression studies, <a href="#48" class="mim-tip-reference" title="Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G. <strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong> J. Med. Genet. 45: 411-419, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>] [<a href="https://doi.org/10.1136/jmg.2007.054635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18310264">Yoon et al. (2008)</a> demonstrated that the H723R mutant protein was retained in the endoplasmic reticulum, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity, but the defects could be rescued considerably by decreased temperature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18310264" 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>.0012 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908363 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908363;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/rs121908363?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=rs121908363" 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=rs121908363" 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=RCV000005096 OR RCV000005097 OR RCV000154350 OR RCV001057908 OR RCV005041983" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005096, RCV000005097, RCV000154350, RCV001057908, RCV005041983" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005096...</a>
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<p>For discussion of the thr721-to-met (T721M) mutation in the SLC26A4 gene that was found in compound heterozygous state in patients with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>) by <a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a>, and in a patient with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>) by <a href="#42" class="mim-tip-reference" title="Tsukamoto, K., Suzuki, H., Harada, D., Namba, A., Abe, S., Usami, S. <strong>Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese.</strong> Europ. J. Hum. Genet. 11: 916-922, 2003. Note: Erratum: Europ. J. Hum. Genet. 12: 422 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14508505</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14508505">Tsukamoto et al. (2003)</a>, see <a href="#0011">605646.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10190331+14508505" 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>.0013 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</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">rs1584317722 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1584317722;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=rs1584317722" 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=rs1584317722" 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=RCV000005084" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005084" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005084</a>
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<p>In 1 family with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>), <a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a> identified a deletion of a single nucleotide, 917T, of the SLC26A4 gene. No mutation was found on the other allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" 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 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</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">rs121908364 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908364;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=rs121908364" 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=rs121908364" 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=RCV000005092" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005092" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005092</a>
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<p>In families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>), <a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a> identified a C-to-T transition at nucleotide 1115 of the SLC26A4 gene, leading to an ala-to-val substitution at residue 372 (A372V). This mutation was found in compound heterozygosity with the 2111insGCTGG mutation (<a href="#0015">605646.0015</a>) in 1 family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" 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>.0015 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
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SLC26A4, 5-BP INS, NT2111
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554362735 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554362735;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=rs1554362735" 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=rs1554362735" 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=RCV000515662" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000515662" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000515662</a>
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<p>For discussion of the 5-bp insertion in the SLC26A4 gene (2111insGCTGG) that was found in compound heterozygous state in patients with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>) by <a href="#43" class="mim-tip-reference" title="Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. <strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong> Hum. Genet. 104: 188-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>] [<a href="https://doi.org/10.1007/s004390050933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10190331">Usami et al. (1999)</a>, see <a href="#0014">605646.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" 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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SLC26A4, 1-BP DEL, 279T
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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> rs786204421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204421;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/rs786204421?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=rs786204421" 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=rs786204421" 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=RCV000169009 OR RCV000507613 OR RCV001069158 OR RCV003474895 OR RCV005042348" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169009, RCV000507613, RCV001069158, RCV003474895, RCV005042348" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169009...</a>
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<p><a href="#23" class="mim-tip-reference" title="Kopp, P., Karamanoglu Arseven, O., Sabacan, L., Kotlar, T., Dupuis, J., Cavaliere, H., Santos, C. L. S., Jameson, J. L., Medeiros-Neto, G. <strong>Phenocopies for deafness and goiter development in a large inbred Brazilian kindred with Pendred's syndrome associated with a novel mutation in the PDS gene.</strong> J. Clin. Endocr. Metab. 84: 336-341, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9920104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9920104</a>] [<a href="https://doi.org/10.1210/jcem.84.1.5398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9920104">Kopp et al. (1999)</a> studied a consanguineous kindred from northeastern Brazil for features of Pendred syndrome (PDS; <a href="/entry/274600">274600</a>). The index patient, with the classic triad of deafness, positive perchlorate test, and goiter, was found to be homozygous for a deletion of thymidine at position 279 (279delT) in exon 3 of the SLC26A4 gene, resulting in a frameshift and premature stop codon at amino acid 96. This mutation truncates the protein in its first transmembrane domain. Two other patients with deafness were homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Palos, F., Garcia-Rendueles, M. E. R., Araujo-Vilar, D., Obregon, M. J., Calvo, R. M., Cameselle-Teijeiro, J., Bravo, S. B., Perez-Guerra, O., Loidi, L., Czarnocka, B., Alvarez, P., Refetoff, S., Dominguez-Gerpe, L., Alvarez, C. V., Lado-Abeal, J. <strong>Pendred syndrome in two Galician families: insights into clinical phenotypes through cellular, genetic, and molecular studies.</strong> J. Clin. Endocr. Metab. 93: 267-277, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17940114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17940114</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17940114[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/10.1210/jc.2007-0539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17940114">Palos et al. (2008)</a> noted that 279delT is a founder mutation in Galicia (northwest Spain). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17940114" 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> rs765884316 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765884316;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/rs765884316?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=rs765884316" 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=rs765884316" 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=RCV000005099 OR RCV003155017 OR RCV003555919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005099, RCV003155017, RCV003555919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005099...</a>
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<p><a href="#26" class="mim-tip-reference" title="Lopez-Bigas, N., Rabionet, R., de Cid, R., Govea, N., Gasparini, P., Zelante, L., Arbones, M. L., Estivill, X. <strong>Splice-site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome.</strong> Hum. Mutat. 14: 520-526, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571950</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<520::AID-HUMU11>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571950">Lopez-Bigas et al. (1999)</a> performed mutation analysis of the individual exons of the SLC26A4 gene in a Spanish Pendred syndrome (PDS; <a href="/entry/274600">274600</a>) family that showed intrafamilial variability of the deafness phenotype (2 patients with profound and 1 with moderate to severe deafness). They identified a new splice site mutation affecting intron 4 at nucleotide position 639+7. RNA analysis from lymphocytes of the affected patients showed that mutation 639+7A-G generated a new donor splice site, leading to an mRNA with an insertion of 6 nucleotides from intron 4 of SLC26A4. Since the newly created donor splice site was likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the SLC26A4 gene in the cochlea may explain the variability in the deafness presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10571950" 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> rs111033307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033307;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/rs111033307?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=rs111033307" 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=rs111033307" 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=RCV000005100 OR RCV000036437 OR RCV000413198 OR RCV001004641 OR RCV005041984" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005100, RCV000036437, RCV000413198, RCV001004641, RCV005041984" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005100...</a>
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<p><a href="#27" class="mim-tip-reference" title="Masmoudi, S., Charfedine, I., Hmani, M., Grati, M., Ghorbel, A. M., Elgaied-Boulila, A., Drira, M., Hardelin, J.-P., Ayadi, M. <strong>Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation.</strong> Am. J. Med. Genet. 90: 38-44, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602116</a>]" pmid="10602116">Masmoudi et al. (2000)</a> performed molecular analysis of the SLC26A4 gene in 2 large consanguineous families from southern Tunisia with a total of 23 individuals who had profound congenital deafness (see PDS, <a href="/entry/274600">274600</a>); the same missense mutation, leu445-to-trp (L445W), was identified in all affected individuals. A widened vestibular aqueduct was found in all patients who underwent CT scan of the inner ear. In contrast, goiter was present in only 11 affected individuals; 8 of these patients who were tested had a normal result on perchlorate discharge test. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10602116" 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="Choi, B. Y., Stewart, A. K., Madeo, A. C., Pryor, S. P., Lenhard, S., Kittles, R., Eisenman, D., Kim, H. J., Niparko, J., Thomsen, J., Arnos, K. S., Nance, W. E., and 9 others. <strong>Hypo-functioning SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?</strong> Hum. Mutat. 30: 599-608, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19204907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19204907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19204907[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/10.1002/humu.20884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19204907">Choi et al. (2009)</a> used in vitro functional expression studies in COS-7 cells to show that the mutant L445W protein was retained in the endoplasmic reticulum and not expressed at the cell surface, confirming its pathogenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19204907" 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> rs111033348 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033348;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/rs111033348?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=rs111033348" 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=rs111033348" 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=RCV000005101 OR RCV000036499 OR RCV000225014 OR RCV000770869 OR RCV000824763 OR RCV001389159" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005101, RCV000036499, RCV000225014, RCV000770869, RCV000824763, RCV001389159" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005101...</a>
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<p>In a Druze family, <a href="#1" class="mim-tip-reference" title="Adato, A., Raskin, L., Petit, C., Bonne-Tamir, B. <strong>Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus.</strong> Europ. J. Hum. Genet. 8: 437-442, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10878664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10878664</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10878664">Adato et al. (2000)</a> found a C-to-T transition at nucleotide 801 in exon 5 of the SLC26A4 gene, predicted to result in a thr193-to-ile amino acid substitution in the protein. Members of this family were first diagnosed with recessive nonsyndromic hearing loss (<a href="#5" class="mim-tip-reference" title="Baldwin, C. T., Weiss, S., Farrer, L., De Stefano, A., Adair, R., Franklyn, B., Kidd, K. K., Korostishevsky, M., Bonne-Tamir, B. <strong>Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population.</strong> Hum. Molec. Genet. 4: 1637-1642, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541853</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541853">Baldwin et al., 1995</a>), i.e., DFNB4 (see <a href="/entry/600791">600791</a>). Subsequent tests showed that they had goiter and therefore the diagnosis was changed to Pendred syndrome (PDS; <a href="/entry/274600">274600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10878664+8541853" 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=RCV000036426 OR RCV000169097 OR RCV000225034 OR RCV000802527 OR RCV001291249 OR RCV002496558" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036426, RCV000169097, RCV000225034, RCV000802527, RCV001291249, RCV002496558" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036426...</a>
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<p><a href="#18" class="mim-tip-reference" title="Fugazzola, L., Mannavola, D., Cerutti, N., Maghnie, M., Pagella, F., Bianchi, P., Weber, G., Persani, L., Beck-Peccoz, P. <strong>Molecular analysis of the Pendred's syndrome gene and magnetic resonance imaging studies of the inner ear are essential for the diagnosis of true Pendred's syndrome.</strong> J. Clin. Endocr. Metab. 85: 2469-2475, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10902795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10902795</a>] [<a href="https://doi.org/10.1210/jcem.85.7.6694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10902795">Fugazzola et al. (2000)</a> studied 3 Italian families presenting with the clinical features of Pendred syndrome (PDS; <a href="/entry/274600">274600</a>). One subject, the only patient with enlargement of vestibular aqueduct and endolymphatic duct and sac at MRI, was compound heterozygous for a deletion in exon 10 of the SLC26A4 gene (1197delT) and a 1-bp insertion in exon 9 (<a href="#0021">605646.0021</a>). The 1197delT mutation leads to a frameshift at codon 400, followed by premature termination at codon 431. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10902795" 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">rs1584344687 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1584344687;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=rs1584344687" 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=rs1584344687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The second mutation in the compound heterozygous patient with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>) reported by <a href="#18" class="mim-tip-reference" title="Fugazzola, L., Mannavola, D., Cerutti, N., Maghnie, M., Pagella, F., Bianchi, P., Weber, G., Persani, L., Beck-Peccoz, P. <strong>Molecular analysis of the Pendred's syndrome gene and magnetic resonance imaging studies of the inner ear are essential for the diagnosis of true Pendred's syndrome.</strong> J. Clin. Endocr. Metab. 85: 2469-2475, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10902795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10902795</a>] [<a href="https://doi.org/10.1210/jcem.85.7.6694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10902795">Fugazzola et al. (2000)</a> (see <a href="#0020">605646.0020</a>) was a single-basepair insertion in nucleotide 2182 in exon 19 (2182-2183insG), resulting in a stop codon at position 728 (tyr728 to ter; Y728X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10902795" 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">rs2129315781 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2129315781;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=rs2129315781" 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=rs2129315781" 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=RCV000005104 OR RCV003472969" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005104, RCV003472969" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005104...</a>
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<p>In a 4-year-old boy with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>) who presented with a solitary thyroid nodule, <a href="#28" class="mim-tip-reference" title="Massa, G., Jaenen, N., de Varebeke, S. J., Peeters, N., Wuyts, W. <strong>Solitary thyroid nodule as presenting symptom of Pendred syndrome caused by a novel splice-site mutation in intron 8 of the SLC26A4 gene.</strong> Europ. J. Pediat. 162: 674-677, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920581</a>] [<a href="https://doi.org/10.1007/s00431-003-1281-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920581">Massa et al. (2003)</a> identified homozygosity for a splice site mutation (1002-4C-G) in intron 8 of the SLC26A4 gene, resulting in a putative truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920581" 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>.0023 PENDRED SYNDROME</strong>
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SLC26A4, SER133THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908365 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908365;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=rs121908365" 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=rs121908365" 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=RCV000005105 OR RCV001004622 OR RCV001851661" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005105, RCV001004622, RCV001851661" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005105...</a>
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<p>In a nonconsanguineous family of Turkish origin with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#7" class="mim-tip-reference" title="Borck, G., Roth, C., Martine, U., Wildhardt, G., Pohlenz, J. <strong>Mutations in the PDS gene in German families with Pendred's syndrome: V138F is a founder mutation.</strong> J. Clin. Endocr. Metab. 88: 2916-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788906</a>] [<a href="https://doi.org/10.1210/jc.2002-021334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788906">Borck et al. (2003)</a> found homozygosity for a T-to-A transversion in exon 4 of the SLC26A4 gene, which resulted in replacement of a serine residue by threonine (S133T) in the second predicted transmembrane domain of pendrin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788906" 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="0024" class="mim-anchor"></a>
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<strong>.0024 PENDRED SYNDROME</strong>
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SLC26A4, VAL138PHE
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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> rs111033199 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033199;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/rs111033199?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=rs111033199" 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=rs111033199" 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=RCV000005106 OR RCV000036493 OR RCV000413949 OR RCV000824762 OR RCV001375189 OR RCV001813952 OR RCV004528079" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005106, RCV000036493, RCV000413949, RCV000824762, RCV001375189, RCV001813952, RCV004528079" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005106...</a>
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<p>In 3 German families with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#7" class="mim-tip-reference" title="Borck, G., Roth, C., Martine, U., Wildhardt, G., Pohlenz, J. <strong>Mutations in the PDS gene in German families with Pendred's syndrome: V138F is a founder mutation.</strong> J. Clin. Endocr. Metab. 88: 2916-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788906</a>] [<a href="https://doi.org/10.1210/jc.2002-021334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788906">Borck et al. (2003)</a> found a G-to-T transversion in exon 4 of the SLC26A4 gene resulting in a val138-to-phe (V138F) substitution in pendrin. One patient was homozygous for the mutation; the patients from the other families were compound heterozygous. <a href="#7" class="mim-tip-reference" title="Borck, G., Roth, C., Martine, U., Wildhardt, G., Pohlenz, J. <strong>Mutations in the PDS gene in German families with Pendred's syndrome: V138F is a founder mutation.</strong> J. Clin. Endocr. Metab. 88: 2916-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788906</a>] [<a href="https://doi.org/10.1210/jc.2002-021334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788906">Borck et al. (2003)</a> demonstrated that V138F is a founder mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788906" 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="0025" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0025 PENDRED SYNDROME</strong>
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</h4>
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SLC26A4, TYR530HIS
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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> rs111033254 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033254;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/rs111033254?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=rs111033254" 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=rs111033254" 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=RCV000005107 OR RCV000036449 OR RCV001229712 OR RCV003472970 OR RCV005031392" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005107, RCV000036449, RCV001229712, RCV003472970, RCV005031392" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005107...</a>
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<p>In 2 sibs from a German family with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#7" class="mim-tip-reference" title="Borck, G., Roth, C., Martine, U., Wildhardt, G., Pohlenz, J. <strong>Mutations in the PDS gene in German families with Pendred's syndrome: V138F is a founder mutation.</strong> J. Clin. Endocr. Metab. 88: 2916-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788906</a>] [<a href="https://doi.org/10.1210/jc.2002-021334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788906">Borck et al. (2003)</a> demonstrated compound heterozygosity for a V138F substitution (<a href="#0024">605646.0024</a>) and a T-to-C transition in exon 14 of the SLC26A4 gene resulting in a tyr-to-his change at residue 530 (Y530H). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788906" 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="Choi, B. Y., Stewart, A. K., Madeo, A. C., Pryor, S. P., Lenhard, S., Kittles, R., Eisenman, D., Kim, H. J., Niparko, J., Thomsen, J., Arnos, K. S., Nance, W. E., and 9 others. <strong>Hypo-functioning SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?</strong> Hum. Mutat. 30: 599-608, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19204907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19204907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19204907[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/10.1002/humu.20884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19204907">Choi et al. (2009)</a> used in vitro functional expression studies in COS-7 cells to show that the mutant Y530H protein had intracellular trafficking defects, resulting in partial retention in the endoplasmic reticulum and some post-ER locations, confirming its pathogenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19204907" 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="0026" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0026 PENDRED SYNDROME</strong>
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SLC26A4, GLU384GLY
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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> rs111033244 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033244;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/rs111033244?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=rs111033244" 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=rs111033244" 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=RCV000005089 OR RCV000036425 OR RCV000520205 OR RCV001095693 OR RCV002482829 OR RCV004528076" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005089, RCV000036425, RCV000520205, RCV001095693, RCV002482829, RCV004528076" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005089...</a>
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<span class="mim-text-font">
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<p>In 2 sibs from a German family with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>), <a href="#7" class="mim-tip-reference" title="Borck, G., Roth, C., Martine, U., Wildhardt, G., Pohlenz, J. <strong>Mutations in the PDS gene in German families with Pendred's syndrome: V138F is a founder mutation.</strong> J. Clin. Endocr. Metab. 88: 2916-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788906</a>] [<a href="https://doi.org/10.1210/jc.2002-021334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788906">Borck et al. (2003)</a> demonstrated compound heterozygosity for a V138F substitution (<a href="#0024">605646.0024</a>) and an A-to-G transition in exon 10 of the SLC26A4 gene resulting in a glu-to-gly change at residue 384 (E384G). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788906" 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="0027" class="mim-anchor"></a>
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<strong>.0027 PENDRED SYNDROME</strong>
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DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs60284988 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs60284988;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/rs60284988?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=rs60284988" 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=rs60284988" 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=RCV000005109 OR RCV000005110 OR RCV000154443 OR RCV000412985 OR RCV001375210 OR RCV004528080" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005109, RCV000005110, RCV000154443, RCV000412985, RCV001375210, RCV004528080" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005109...</a>
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<p>In 9 patients with Pendred syndrome (PDS; <a href="/entry/274600">274600</a>) or nonsyndromic autosomal deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>), <a href="#47" class="mim-tip-reference" title="Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. <strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong> Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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/10.1086/518314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503324">Yang et al. (2007)</a> identified heterozygosity for a -103T-C transition in a key regulatory element in the 5-prime UTR of the SLC26A4 gene. The mutation completely abolished transcriptional activation of the SLC26A4 gene by FOXI1 (<a href="/entry/601093">601093</a>). The authors stated that although they failed to identify a second SLC26A4 mutation in these families, it is not uncommon to detect a single disease-causing mutation presumably in combination with a unidentified mutation either in cis or in trans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17503324" 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>.0028 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs111033205 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033205;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/rs111033205?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=rs111033205" 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=rs111033205" 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=RCV000005111 OR RCV000036509 OR RCV000169251 OR RCV000656195 OR RCV001040420 OR RCV002496264 OR RCV004528081" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005111, RCV000036509, RCV000169251, RCV000656195, RCV001040420, RCV002496264, RCV004528081" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005111...</a>
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<p><a href="#47" class="mim-tip-reference" title="Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. <strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong> Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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/10.1086/518314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503324">Yang et al. (2007)</a> described a girl with nonsyndromic autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>) who was doubly heterozygous for a glu29-to-gln (E29Q) mutation in SLC26A4 and a gly258-to-glu (G258E) missense mutation in FOXI1 (<a href="/entry/601093#0001">601093.0001</a>). The unaffected parents were each heterozygous for 1 of the mutations, respectively, and her unaffected sister carried only the E29Q mutation in SLC26A4. <a href="#47" class="mim-tip-reference" title="Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. <strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong> Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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/10.1086/518314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503324">Yang et al. (2007)</a> suggested that although other inheritance patterns, such as FOXI1 compound heterozygosity with a yet-to-be-identified FOXI1 mutation, could not be completely excluded, the pathogenicity of the double-heterozygous genotype was supported by several facts. First, the mouse mutant that is a double heterozygote for mutations in these 2 genes has a similar phenotype (<a href="#22" class="mim-tip-reference" title="Hulander, M., Kiernan, A. E., Blomqvist, S. R., Carlsson, P., Samuelsson, E. J., Johansson, B. R., Steel, K. P., Enerback, S. <strong>Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice.</strong> Development 130: 2013-2025, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12642503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12642503</a>] [<a href="https://doi.org/10.1242/dev.00376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12642503">Hulander et al., 2003</a>). Second, the FOXI1 G258E mutation reduced transcription of SLC26A4 in vitro. Third, the SLC26A4 E29Q mutation had been reported previously in families segregating Pendred syndrome in association with other SLC26A4 mutations. Fourth, both the affected and the unaffected child had identical SLC26A4 genotypes, which was consistent with the presence of an additional genetic modifier in the affected child. Fifth, neither of these mutations had been reported in screens of 500 chromosomes. <a href="#47" class="mim-tip-reference" title="Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. <strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong> Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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/10.1086/518314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503324">Yang et al. (2007)</a> concluded that this was the first example of digenic inheritance to be verified as a cause of human deafness. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17503324+12642503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Pera, A., Villamar, M., Vinuela, A., Gandia, M., Meda, C., Moreno, F., Hernandez-Chico, C. <strong>A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.</strong> Europ. J. Hum. Genet. 16: 888-896, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285825</a>] [<a href="https://doi.org/10.1038/ejhg.2008.30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285825">Pera et al. (2008)</a> identified the E29Q variant in 1 of 214 Spanish control individuals with normal hearing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285825" 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>.0029 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
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DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC, INCLUDED
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SLC26A4, IVS7AS, A-G, -2
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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> rs111033313 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033313;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/rs111033313?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=rs111033313" 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=rs111033313" 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=RCV000005112 OR RCV000036513 OR RCV000169120 OR RCV000414330 OR RCV000824767 OR RCV001291247 OR RCV004737136" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005112, RCV000036513, RCV000169120, RCV000414330, RCV000824767, RCV001291247, RCV004737136" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005112...</a>
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<p>In Chinese patients with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>), <a href="#45" class="mim-tip-reference" title="Wang, Q.-J., Zhao, Y.-L., Rao, S.-Q., Guo, Y.-F., Yuan, H., Zong, L., Guan, J., Xu, B.-C., Wang, D.-Y., Han, M.-K., Lan, L., Zhai, S.-Q., Shen, Y. <strong>A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China.</strong> Clin. Genet. 72: 245-254, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17718863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17718863</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00862.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17718863">Wang et al. (2007)</a> identified an A-to-G transition in intron 7 of the SLC26A4 gene, resulting in the skipping of exon 8. This mutation was the most commonly identified, accounting for 57.6% of mutant alleles in 93 simplex families with enlarged vestibular aqueduct (EVA). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17718863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Park, H.-J., Lee, S.-J., Jin, H.-S., Lee, J. O., Go, S.-H., Jang, H. S., Moon, S.-K., Lee, S.-C., Chun, Y.-M., Lee, H.-K., Choi, J.-Y., Jung, S.-C., Griffith, A. J., Koo, S. K. <strong>Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans.</strong> Clin. Genet. 67: 160-165, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15679828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15679828</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00386.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15679828">Park et al. (2005)</a> identified the IVS7-2A-G splice site mutation in 9 (20%) of 45 mutant alleles in a study of Korean DFNB4 with EVA patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15679828" 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 15 patients from 13 unrelated Chinese families with deafness and EVA, <a href="#21" class="mim-tip-reference" title="Hu, H., Wu, L., Feng, Y., Pan, Q., Long, Z., Li, J., Dai, H., Xia, K., Liang, D., Niikawa, N., Xia, J. <strong>Molecular analysis of hearing loss associated with enlarged vestibular aqueduct in the mainland Chinese: a unique SLC26A4 mutation spectrum.</strong> J. Hum. Genet. 52: 492-497, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17443271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17443271</a>] [<a href="https://doi.org/10.1007/s10038-007-0139-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17443271">Hu et al. (2007)</a> identified the IVS7-2A-G mutation in 5 (22.3%) of 22 mutant alleles. The mutation was found either in homozygosity or compound heterozygosity. Reviewing previously published studies involving Chinese patients, the authors stated that IVS7-2A-G accounted for 69.1% (76 of 110) of all mutant alleles in the Chinese, suggesting a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17443271" 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="#46" class="mim-tip-reference" title="Yang, T., Gurrola, J. G., II, Wu, H., Chiu, S. M., Wangemann, P., Snyder, P. M., Smith, R. J. H. <strong>Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.</strong> Am. J. Hum. Genet. 84: 651-657, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19426954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19426954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19426954[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19426954">Yang et al. (2009)</a> identified double heterozygosity for this mutation in SLC26A4 (919-2A-G) and a missense mutation in the KCNJ10 gene (R348C; <a href="/entry/602208#0009">602208.0009</a>). The findings were consistent with digenic inheritance of DFNB4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19426954" 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>.0030 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</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">rs121908366 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908366;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=rs121908366" 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=rs121908366" 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=RCV000005113 OR RCV001753402 OR RCV002476930 OR RCV002512793" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005113, RCV001753402, RCV002476930, RCV002512793" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005113...</a>
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<p>In 5 of 127 Spanish probands with enlarged vestibular aqueduct and hearing loss (DFNB4; <a href="/entry/600791">600791</a>), <a href="#33" class="mim-tip-reference" title="Pera, A., Villamar, M., Vinuela, A., Gandia, M., Meda, C., Moreno, F., Hernandez-Chico, C. <strong>A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.</strong> Europ. J. Hum. Genet. 16: 888-896, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285825</a>] [<a href="https://doi.org/10.1038/ejhg.2008.30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285825">Pera et al. (2008)</a> identified a 1541C-A transversion in exon 13 of the SLC6A4 gene, resulting in a gln514-to-lys (Q514K) substitution. The Q514K substitution was the most prevalent SLC26A4 mutation in this cohort, accounting for 6 (17%) of 36 mutated alleles. Haplotype analysis indicated a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285825" 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>.0031 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs111033212 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033212;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/rs111033212?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=rs111033212" 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=rs111033212" 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=RCV000005114 OR RCV000036420 OR RCV000576732 OR RCV000656976 OR RCV000824769 OR RCV002291265" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005114, RCV000036420, RCV000576732, RCV000656976, RCV000824769, RCV002291265" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005114...</a>
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<p>In a patient with nonsyndromic hearing loss associated with enlarged vestibular aqueduct (DFNB4; <a href="/entry/600791">600791</a>), <a href="#46" class="mim-tip-reference" title="Yang, T., Gurrola, J. G., II, Wu, H., Chiu, S. M., Wangemann, P., Snyder, P. M., Smith, R. J. H. <strong>Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.</strong> Am. J. Hum. Genet. 84: 651-657, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19426954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19426954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19426954[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19426954">Yang et al. (2009)</a> identified double heterozygosity for a T-to-C transition at nucleotide 1003 of the SLC26A4 gene, resulting in a phe-to-leu substitution at codon 335 (F335L), and a missense mutation in the KCNJ10 gene (P194H; <a href="/entry/602208#0008">602208.0008</a>). The F335L mutation had been described by <a href="#34" class="mim-tip-reference" title="Pryor, S. P., Madeo, A. C., Reynolds, J. C., Sarlis, N. J., Arnos, K. S., Nance, W. E., Yang, Y., Zalewski, C. K., Brewer, C. C., Butman, J. A., Griffith, A. J. <strong>SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. (Letter)</strong> J. Med. Genet. 42: 159-165, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689455</a>] [<a href="https://doi.org/10.1136/jmg.2004.024208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689455">Pryor et al. (2005)</a> and was been reported in 14 of 668 patients with enlarged vestibular aqueduct (EVA)-associated hearing loss but in none of 358 normal hearing controls, as described by <a href="#46" class="mim-tip-reference" title="Yang, T., Gurrola, J. G., II, Wu, H., Chiu, S. M., Wangemann, P., Snyder, P. M., Smith, R. J. H. <strong>Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.</strong> Am. J. Hum. Genet. 84: 651-657, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19426954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19426954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19426954[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.04.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19426954">Yang et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15689455+19426954" 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="Choi, B. Y., Stewart, A. K., Madeo, A. C., Pryor, S. P., Lenhard, S., Kittles, R., Eisenman, D., Kim, H. J., Niparko, J., Thomsen, J., Arnos, K. S., Nance, W. E., and 9 others. <strong>Hypo-functioning SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?</strong> Hum. Mutat. 30: 599-608, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19204907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19204907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19204907[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/10.1002/humu.20884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19204907">Choi et al. (2009)</a> used in vitro functional expression studies in COS-7 cells to show that the mutant F335L protein was expressed normally at the cell surface and retained function in Xenopus oocytes. The authors suggested that it may not be pathogenic as a monoallelic variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19204907" 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>REFERENCES</strong>
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Adato, A., Raskin, L., Petit, C., Bonne-Tamir, B.
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<strong>Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus.</strong>
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Europ. J. Hum. Genet. 8: 437-442, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10878664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10878664</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10878664" 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.5200489" target="_blank">Full Text</a>]
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Albert, S., Blons, H., Jonard, L., Feldmann, D., Chauvin, P., Loundon, N., Sergent-Allaoui, A., Houang, M., Joannard, A., Schmerber, S., Delobel, B., Leman, J., and 18 others.
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<strong>SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations.</strong>
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Europ. J. Hum. Genet. 14: 773-779, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16570074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16570074</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16570074" 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.5201611" target="_blank">Full Text</a>]
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Anwar, S., Riazuddin, S., Ahmed, Z. M., Tasneem, S., Jaleel, A., Khan, S. Y., Griffith, A. J., Friedman, T. B., Riazuddin, S.
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<strong>SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis.</strong>
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J. Hum. Genet. 54: 266-270, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19287372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19287372</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19287372" 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/jhg.2009.21" target="_blank">Full Text</a>]
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Azaiez, H., Yang, T., Prasad, S., Sorensen, J. L., Nishimura, C. J., Kimberling, W. J., Smith, R. J. H.
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<strong>Genotype-phenotype correlations for SLC26A4-related deafness.</strong>
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Hum. Genet. 122: 451-457, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17690912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17690912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17690912[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=17690912" 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/s00439-007-0415-2" target="_blank">Full Text</a>]
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Baldwin, C. T., Weiss, S., Farrer, L., De Stefano, A., Adair, R., Franklyn, B., Kidd, K. K., Korostishevsky, M., Bonne-Tamir, B.
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<strong>Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population.</strong>
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[<a href="https://doi.org/10.1210/jc.2002-021334" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1116" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2017-104721" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20884" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.7.1105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.25.22.10171-10182.2005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0378-1119(98)00261-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-007-0139-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/dev.00376" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.1.5398" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.7.5973" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0398-215" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<520::AID-HUMU11>3.0.CO;2-K" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00431-003-1281-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2004-1013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2004.00386.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.40.4.242" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2008.30" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.024208" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/qjmed/90.7.443" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12354788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12354788</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12354788" 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/11.21.2625" target="_blank">Full Text</a>]
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<a id="Royaux2001" class="mim-anchor"></a>
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<div class="">
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Royaux, I. E., Wall, S. M., Karniski, L. P., Everett, L. A., Suzuki, K., Knepper, M. A., Green, E. D.
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<strong>Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11274445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11274445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11274445[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=11274445" 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.071516798" target="_blank">Full Text</a>]
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<a id="Scott2000" class="mim-anchor"></a>
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Scott, D. A., Wang, R., Kreman, T. M., Andrews, M., McDonald, J. M., Bishop, J. R., Smith, R. J. H., Karniski, L. P., Sheffield, V. C.
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<strong>Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).</strong>
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Hum. Molec. Genet. 9: 1709-1715, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861298</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/9.11.1709" target="_blank">Full Text</a>]
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<a id="39" class="mim-anchor"></a>
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<a id="Scott1999" class="mim-anchor"></a>
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<div class="">
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Scott, D. A., Wang, R., Kreman, T. M., Sheffield, V. C., Karniski, L. P.
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<strong>The Pendred syndrome gene encodes a chloride-iodide transport protein.</strong>
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Nature Genet. 21: 440-443, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10192399" 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/10.1038/7783" target="_blank">Full Text</a>]
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<a id="Taylor2002" class="mim-anchor"></a>
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Taylor, J. P., Metcalfe, R. A., Watson, P. F., Weetman, A. P., Trembath, R. C.
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<strong>Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome.</strong>
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J. Clin. Endocr. Metab. 87: 1778-1784, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932316</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932316" 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/10.1210/jcem.87.4.8435" target="_blank">Full Text</a>]
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<a id="Tekin2003" class="mim-anchor"></a>
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<div class="">
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Tekin, M., Akcayoz, D., Comak, E., Bogoclu, G., Duman, T., Fitoz, S., Ilhan, I., Akar, N.
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<strong>Screening the SLC26A4 gene in probands with deafness and goiter (Pendred syndrome) ascertained from a large group of students of the schools for the deaf in Turkey. (Letter)</strong>
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Clin. Genet. 64: 371-374, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12974744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12974744</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12974744" 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/10.1034/j.1399-0004.2003.00144.x" target="_blank">Full Text</a>]
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Tsukamoto, K., Suzuki, H., Harada, D., Namba, A., Abe, S., Usami, S.
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<strong>Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese.</strong>
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Europ. J. Hum. Genet. 11: 916-922, 2003. Note: Erratum: Europ. J. Hum. Genet. 12: 422 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14508505</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14508505" 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.5201073" target="_blank">Full Text</a>]
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<a id="Usami1999" class="mim-anchor"></a>
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Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J.
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<strong>Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations.</strong>
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Hum. Genet. 104: 188-192, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10190331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10190331</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10190331" 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/s004390050933" target="_blank">Full Text</a>]
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<a id="Van Hauwe1998" class="mim-anchor"></a>
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Van Hauwe, P., Everett, L. A., Coucke, P., Scott, D. A., Kraft, M. L., Ris-Stalpers, C., Bolder, C., Otten, B., de Vijlder, J. J. M., Dietrich, N. L., Ramesh, A., Srisailapathy, S. C. R., Parving, A., Cremers, C. W. R. J., Willems, P. J., Smith, R. J. H., Green, E. D., Van Camp, G.
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<strong>Two frequent missense mutations in Pendred syndrome.</strong>
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Hum. Molec. Genet. 7: 1099-1104, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618166</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618166" 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/7.7.1099" target="_blank">Full Text</a>]
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<a id="Wang2007" class="mim-anchor"></a>
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Wang, Q.-J., Zhao, Y.-L., Rao, S.-Q., Guo, Y.-F., Yuan, H., Zong, L., Guan, J., Xu, B.-C., Wang, D.-Y., Han, M.-K., Lan, L., Zhai, S.-Q., Shen, Y.
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<strong>A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China.</strong>
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Clin. Genet. 72: 245-254, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17718863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17718863</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17718863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00862.x" target="_blank">Full Text</a>]
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<a id="Yang2009" class="mim-anchor"></a>
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Yang, T., Gurrola, J. G., II, Wu, H., Chiu, S. M., Wangemann, P., Snyder, P. M., Smith, R. J. H.
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<strong>Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.</strong>
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Am. J. Hum. Genet. 84: 651-657, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19426954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19426954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19426954[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=19426954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2009.04.014" target="_blank">Full Text</a>]
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Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H.
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<strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong>
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Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503324[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=17503324" 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/10.1086/518314" target="_blank">Full Text</a>]
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Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G.
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<strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong>
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J. Med. Genet. 45: 411-419, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18310264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18310264</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18310264" 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.2007.054635" target="_blank">Full Text</a>]
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<a id="Yoshida2002" class="mim-anchor"></a>
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Yoshida, A., Taniguchi, S., Hisatome, I., Royaux, I. E., Green, E. D., Kohn, L. D., Suzuki, K.
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<strong>Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells.</strong>
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J. Clin. Endocr. Metab. 87: 3356-3361, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12107249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12107249</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12107249" 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/10.1210/jcem.87.7.8679" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/06/2019
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 2/16/2012<br>Cassandra L. Kniffin - updated : 1/19/2011<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Ada Hamosh - updated : 10/6/2009<br>Marla J. F. O'Neill - updated : 6/29/2009<br>Marla J. F. O'Neill - updated : 6/1/2009<br>John A. Phillips, III - updated : 5/11/2009<br>Cassandra L. Kniffin - updated : 10/6/2008<br>Cassandra L. Kniffin - updated : 8/19/2008<br>Marla J. F. O'Neill - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 10/26/2007<br>Marla J. F. O'Neill - updated : 8/9/2007<br>Victor A. McKusick - updated : 5/23/2007<br>Marla J. F. O'Neill - updated : 8/29/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>John A. Phillips, III - updated : 4/13/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>John A. Phillips, III - updated : 8/19/2004<br>Marla J. F. O'Neill - updated : 6/2/2004<br>George E. Tiller - updated : 2/4/2004<br>John A. Phillips, III - updated : 2/3/2004<br>Victor A. McKusick - updated : 1/22/2004<br>Victor A. McKusick - updated : 11/4/2003<br>John A. Phillips, III - updated : 12/4/2002<br>John A. Phillips, III - updated : 10/10/2002<br>Victor A. McKusick - updated : 6/25/2001<br>Victor A. McKusick - updated : 4/17/2001<br>George E. Tiller - updated : 3/13/2001<br>John A. Phillips, III - updated : 2/20/2001
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Creation Date:
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Victor A. McKusick : 2/14/2001
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carol : 05/08/2024
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alopez : 02/15/2024<br>alopez : 01/26/2024<br>alopez : 01/26/2024<br>carol : 03/07/2019<br>alopez : 03/06/2019<br>carol : 10/04/2016<br>alopez : 04/23/2015<br>mcolton : 4/14/2015<br>carol : 8/30/2013<br>alopez : 6/13/2012<br>ckniffin : 6/12/2012<br>carol : 2/16/2012<br>ckniffin : 2/16/2012<br>wwang : 2/4/2011<br>ckniffin : 1/19/2011<br>alopez : 1/6/2011<br>wwang : 8/20/2010<br>ckniffin : 8/16/2010<br>wwang : 10/27/2009<br>wwang : 10/13/2009<br>alopez : 10/13/2009<br>terry : 10/6/2009<br>wwang : 7/17/2009<br>terry : 6/29/2009<br>wwang : 6/2/2009<br>terry : 6/1/2009<br>alopez : 5/11/2009<br>wwang : 10/10/2008<br>ckniffin : 10/6/2008<br>wwang : 8/28/2008<br>ckniffin : 8/19/2008<br>wwang : 3/25/2008<br>terry : 3/18/2008<br>alopez : 3/10/2008<br>wwang : 11/7/2007<br>ckniffin : 10/26/2007<br>carol : 8/22/2007<br>alopez : 8/9/2007<br>alopez : 8/9/2007<br>alopez : 5/23/2007<br>terry : 5/23/2007<br>wwang : 8/30/2006<br>terry : 8/29/2006<br>mgross : 2/3/2006<br>mgross : 2/3/2006<br>terry : 1/27/2006<br>terry : 8/3/2005<br>wwang : 5/11/2005<br>wwang : 4/13/2005<br>wwang : 3/11/2005<br>wwang : 3/8/2005<br>terry : 3/1/2005<br>alopez : 8/19/2004<br>carol : 6/8/2004<br>terry : 6/2/2004<br>carol : 3/16/2004<br>cwells : 2/4/2004<br>alopez : 2/3/2004<br>cwells : 1/23/2004<br>terry : 1/22/2004<br>tkritzer : 11/6/2003<br>terry : 11/4/2003<br>alopez : 12/4/2002<br>alopez : 10/10/2002<br>carol : 2/27/2002<br>carol : 2/27/2002<br>carol : 8/6/2001<br>alopez : 7/11/2001<br>mcapotos : 7/6/2001<br>mcapotos : 7/2/2001<br>terry : 6/25/2001<br>alopez : 4/19/2001<br>terry : 4/17/2001<br>cwells : 3/27/2001<br>cwells : 3/13/2001<br>cwells : 3/12/2001<br>alopez : 2/21/2001<br>alopez : 2/20/2001<br>alopez : 2/20/2001
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<strong>*</strong> 605646
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SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4
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<em>Alternative titles; symbols</em>
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PENDRIN<br />
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PDS GENE
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<strong><em>HGNC Approved Gene Symbol: SLC26A4</em></strong>
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<strong>SNOMEDCT:</strong> 70348004;
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<strong>ICD10CM:</strong> E07.1;
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Cytogenetic location: 7q22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:107,660,828-107,717,809 </span>
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</em>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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7q22.3
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Deafness, autosomal recessive 4, with enlarged vestibular aqueduct
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600791
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Autosomal recessive
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3
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Pendred syndrome
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274600
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Autosomal recessive
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The SLC26A4 gene encodes an anion transporter known as pendrin and is the gene mutant in Pendred syndrome (PDS; 274600) and enlarged vestibular aqueduct (EVA; 600791).</p>
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<strong>Cloning and Expression</strong>
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<p>Everett et al. (1997) used a positional cloning strategy to identify the gene mutated in Pendred syndrome, which had been mapped by linkage to chromosome 7q31. The PDS gene produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, called pendrin by the authors, is closely related to a number of sulfate transporters. Everett et al. (1997) found that the PDS gene encodes a 780-amino acid (86-kD) protein. Sequences resembling that of human pendrin were found across a large taxonomic span, including animals, plants, and yeast, although the 2 closest relatives were the proteins encoded by the human DRA (126650) and DTDST (606718) genes. The proteins within this family are highly hydrophobic; for example, 57% of the amino acids within pendrin are hydrophobic. </p>
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<strong>Gene Structure</strong>
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<p>In a study of the structure of the DRA gene, which is mutant in congenital chloride diarrhea (CLD; 214700), Haila et al. (1998) found that the PDS gene is highly homologous to the DRA gene, with a similar genomic structure, and that it was situated 3-prime of the DRA gene in the same BAC clone. </p>
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<strong>Gene Function</strong>
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<p>Scott et al. (1999) were unable to detect evidence of sulfate transport following expression of pendrin in Xenopus oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus. The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems. Scott et al. (1999) concluded that pendrin functions as a transporter of chloride and iodide, but not of sulfate. </p><p>Kraiem et al. (1999) tested sulfate transport in thyrocytes obtained from PDS patients and found that it was not defective. This suggested that pendrin in fact may not be a sulfate transporter and emphasized the importance of functional studies on this protein. </p><p>Everett et al. (1999) isolated the mouse ortholog of the PDS gene and performed RNA in situ hybridization on mouse inner ears (from 8 days postcoitum to postnatal day 5) to establish the expression pattern of Pds in the developing auditory and vestibular systems. Pds expression was detected throughout the endolymphatic duct and sac, in distinct areas of the utricle and saccule, and in the external sulcus region within the cochlea. This highly discrete expression pattern is unlike that of any other known gene and involves several regions thought to be important for endolymphatic fluid resorption in the inner ear, consistent with the putative functioning of pendrin as an anion transporter. </p><p>Bidart et al. (2000) studied pendrin expression and localization using real-time kinetic quantitative PCR and antipeptide antibodies, respectively, in normal, benign, and malignant human thyroid tissues. The results were then compared to those observed for sodium/iodide symporter (NIS) expression. In normal tissue, pendrin is localized at the apical pole of thyrocytes, in contrast to the basolateral location of NIS. Immunostaining for pendrin was heterogeneous both inside and among follicles. In hyperfunctioning adenomas, the PDS mRNA level was in the normal range, although immunohistochemical analysis showed strong staining in the majority of follicular cells. In hypofunctioning adenomas, mean PDS gene expression was similar to that detected in normal thyroid tissues, but pendrin immunostaining was highly variable. In thyroid carcinomas, PDS gene expression was dramatically decreased, and pendrin immunostaining was low and was positive only in rare tumor cells. This expression profile was similar to that observed for the NIS gene and its protein product. The authors concluded that pendrin is expressed at the apical membrane of thyrocytes and that PDS gene expression is decreased in thyroid carcinomas. </p><p>Scott et al. (2000) compared 3 common Pendred syndrome allele variants with 3 PDS mutations reported only in individuals with nonsyndromic hearing loss. The mutations associated with Pendred syndrome exhibited complete loss of pendrin-induced chloride and iodide transport, while alleles unique to patients with DFNB4 were able to transport both iodide and chloride, albeit at a much lower level than wildtype pendrin. The authors hypothesized that the residual level of anion transport was sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4, a form of deafness also caused by mutations in pendrin (see 600791). They proposed a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space. </p><p>Taylor et al. (2002) investigated the effect of 9 SLC26A4 missense mutations on pendrin localization and iodide transport. Transient expression of green fluorescent protein-tagged pendrin mutant constructs in mammalian cell lines demonstrated appropriate trafficking to the plasma membrane for only 2 mutants. The remaining SLC26A4 mutants appeared to be retained within the endoplasmic reticulum following transfection. Iodide efflux assays were performed. The results indicated loss of pendrin iodide transport for all mislocalizing mutations. However, SLC26A4 mutants are associated with variable thyroid dysfunction in affected subjects. The authors concluded that additional genetic and/or environmental factors influence the thyroid activity in Pendred syndrome. </p><p>The PDS gene has a relatively restricted pattern of expression, with PDS mRNA detected only in thyroid, inner ear, and kidney. Royaux et al. (2001) examined the distribution and function of pendrin in the mammalian kidney. Immunolocalization studies were performed using anti-pendrin polyclonal and monoclonal antibodies. Labeling was detected on the apical surface of a subpopulation of cells within the cortical collecting ducts (CCD) that also express H+-ATPase but not aquaporin-2 (107777), indicating that pendrin is present in intercalated cells of the CCD. Furthermore, pendrin was detected exclusively within the subpopulation of intercalated cells that express the H+-ATPase but not the anion exchanger 1 (AE1; 109270) and that are thought to mediate bicarbonate secretion. The same distribution of pendrin was observed in mouse, rat, and human kidney. However, pendrin was not detected in kidneys from a Pds-knockout mouse. Perfused CCD tubules isolated from alkali-loaded wildtype mice secreted bicarbonate, whereas tubules from alkali-loaded Pds-knockout mice failed to secrete bicarbonate. Together, these studies indicated that pendrin is an apical anion transporter in intercalated cells of CCDs and has an essential role in renal bicarbonate secretion. Neither Pendred syndrome patients nor pendrin-deficient mice had been reported to develop overt acid-based disturbances, such as metabolic alkalosis. This may reflect the fact that the kidney has other means of regulating bicarbonate excretion in the absence of pendrin. Overt abnormalities in acid-base balance in pendrin-deficient humans or mice may be induced under conditions of extensive alkali loading or severe metabolic alkalosis. </p><p>Using COS-7 cells and Chinese hamster ovary (CHO) cells transfected with expression vectors encoding SLC26A4 cDNA, and by comparison with studies using rat thyroid cells, Yoshida et al. (2002) showed that pendrin is an iodide-specific transporter in mammalian cells and is responsible for iodide efflux in the thyroid. </p><p>Dentice et al. (2005) determined that Titf1 (600635) directly controls Slc26a4 expression in rat thyroid. </p>
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<strong>Molecular Genetics</strong>
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<p>In families with Pendred syndrome (PDS; 274600), Everett et al. (1997) found 3 homozygous deleterious mutations in the SLC26A4 gene, each segregating with the disease in the respective families in which they occurred (e.g., 605646.0001). Implicating loss-of-function mutations in the PDS gene as a direct cause of thyroid disease in Pendred syndrome is relatively straightforward, as the gene is heavily expressed in thyroid, a tissue known to produce sulfated proteins. In particular, thyroglobulin (188450), the major secretory product of thyroid follicular cells, is sulfated both on tyrosine residues and asparagine-linked oligosaccharides. Sulfation of thyroglobulin is ubiquitous in organisms ranging from humans to lower eukaryotes, suggesting that this form of posttranslational modification serves an intrinsic role in thyroglobulin function. It had been suggested that thyroglobulin sulfation can influence subsequent iodination of the protein. The role of pendrin in cochlear development is less obvious. Everett et al. (1997) speculated that Pendred syndrome may be more common than previously thought. They pointed out that another recessive locus for deafness, designated DFNB4 (600791), maps to 7q31, the same region as the PDS gene. They considered it likely that the DFNB4 individuals reported actually have Pendred syndrome, rather than mutations in another gene. </p><p>Van Hauwe et al. (1998) performed mutation analysis of the PDS gene in 14 Pendred families originating from 7 countries and identified all mutations. The mutations included 3 single base deletions, 1 splice site mutation, and 10 missense mutations. One missense mutation (leu236 to pro; 605646.0005) was found in homozygous state in 2 consanguineous families and in heterozygous state in 5 additional nonconsanguineous families, thus being present in half the families. Another missense mutation (thr416 to pro; 605646.0006) was found in homozygous state in 1 family and in heterozygous state in 4 families. Pendred patients in 3 nonconsanguineous families were shown to be compound heterozygotes for these 2 frequent mutations. In total, 1 or both of these mutations were found in 9 of the 14 families analyzed. The findings should facilitate molecular diagnosis of Pendred syndrome. </p><p>Coyle et al. (1998) analyzed 56 kindreds, all with features suggestive of a diagnosis of Pendred syndrome. Molecular analysis of the PDS gene identified 47 of the 60 (78%) mutant alleles in 31 families; the families included 3 homozygous consanguineous kindreds and 1 extended family segregating 3 mutant alleles. Four recurrent mutations accounted for 35 (74%) of PDS disease chromosomes detected and haplotype analysis favored common founders rather than mutation hotspots within the PDS gene. A donor splice mutation (1001+1G-A; 605646.0007) was observed in 10 families, in 5 of which descendants could be traced to the northeast of England, the region in which the family described in 1896 by Pendred resided (Reardon et al., 1997). Analysis of parental DNA failed to reveal any de novo mutations in this study cohort, either within the familial or the isolated cases of Pendred syndrome. </p><p>In the index patient with PDS from a consanguineous kindred from northeastern Brazil, Kopp et al. (1999) found homozygosity for a 279delT mutation (605646.0016) in exon 3 of the PDS gene. The index patient showed the classic triad of deafness, positive perchlorate test, and goiter. Two other patients with deafness were homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wildtype allele. Surprisingly, 6 deaf individuals in this kindred were not homozygous for the 279delT mutation; 3 were heterozygous and 3 were homozygous for the wildtype allele, suggesting a probable distinct genetic cause for their deafness. The authors concluded from comparison of phenotypes and genotypes that phenocopies generated by distinct environmental and/or genetic causes were present in this kindred and that the diagnosis of PDS may be difficult without molecular analysis. </p><p>Usami et al. (1999) identified 7 mutations in the PDS gene in 6 families with nonsyndromic congenital high frequency, fluctuating, sometimes progressive sensorineural hearing loss, and enlarged vestibular aqueduct (DFNB4; 600791) diagnosed by CT scan. PCR and direct sequencing of all 21 exons of PDS was undertaken. </p><p>The hearing loss that occurs in Pendred syndrome or in isolation as DFNB4 is associated with temporal bone abnormalities, ranging from isolated enlargement of the vestibular aqueduct (EVA) to Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2.5 turns is replaced by a hypoplastic coil of 1.5 turns. Campbell et al. (2001) found mutations in 5 of 6 multiplex families with EVA (83%) and in 4 of 5 multiplex families with Mondini dysplasia (80%), implying that mutations in the SLC26A4 gene are the major genetic cause of these temporal abnormalities. In their analyses of Pendred syndrome and DFNB4, they found that the 2 most common mutations, T416P (605646.0006) and IVS8+1G-A (605646.0007), were present in 22% and 30% of families, respectively. </p><p>Rotman-Pikielny et al. (2002) studied the intracellular trafficking of fluorescently-tagged chimeras of wildtype pendrin and 3 common natural mutants (L236P, 605646.0005; T416P, 605646.0006; and G384E, 606646.0008) in living cells. Time-lapse imaging, dual color labeling, and fluorescent recovery after photobleaching studies demonstrated that GFP-wildtype pendrin targets to the plasma membrane. In contrast, all 3 mutant proteins were retained in the endoplasmic reticulum (ER) in colocalization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective, as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wildtype pendrin from targeting the plasma membrane. The authors suggested that ER retention and defective plasma membrane targeting of pendrin mutants may play a key role in the pathogenesis of Pendred syndrome. </p><p>Park et al. (2003) PCR amplified and sequenced 7 exons of SLC26A4 in 274 deaf probands from Korea, China, and Mongolia, and identified a total of 9 different mutations among 15 (5.5%) of the probands. Five of the mutations were novel and the other 4 had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with 3 or more affected offspring of consanguineous matings were analyzed for cosegregation of recessive deafness with short tandem repeat (STR) markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4-linked deafness. Eleven mutant alleles were identified in the 318 families, and all 11 were novel. SLC26A4-linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. Park et al. (2003) concluded that approximately 5% of recessive deafness in south Asians and other populations results from mutation events at SLC26A4. </p><p>To evaluate the contribution of the PDS gene (SLC26A4) in the genetic susceptibility of autoimmune thyroid disease (AITD; see 608173), Hadj Kacem et al. (2003) examined 4 microsatellite markers in the gene region. They genotyped 233 unrelated AITD patients, 15 multiplex AITD families, and 154 normal controls. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with Graves disease (GD; 275000) and Hashimoto thyroiditis (HT; 140300), respectively. The family-based association test showed significant association and linkage between AITDs and alleles 121 bp of D7S496 and 173 bp of D7S501. Results obtained by transmission disequilibrium test were in good agreement with those obtained by the family-based association test. Indeed, evidence for linkage and association of allele 121 bp of D7S496 with AITD was confirmed (P = 0.0114). The authors concluded that SLC26A4 should be considered a susceptibility gene to AITDs with varying contributions in each pathology. </p><p>Albert et al. (2006) analyzed the SLC26A4 gene in 109 patients from 100 unrelated French Caucasian families with nonsyndromic deafness and enlarged vestibular aqueduct and no mutation in the GJB2 gene (121011). They identified 91 allelic variants in 40 unrelated families (prevalence of SLC26A4 mutations, 40%). Albert et al. (2006) estimated that up to 4% of nonsyndromic hearing impairment could be caused by SLC26A4 mutations. </p><p>Wang et al. (2007) identified 40 different SLC26A4 mutations, including 25 novel mutations, among 107 Chinese patients from 101 families with EVA. A splice site mutation (605646.0029) in intron 7 was the most common mutation, accounting for 57.6% of the mutant alleles. </p><p>Among 105 Spanish patients from 47 families with Pendred syndrome or nonsyndromic EVA and 20 families with recessive nonsyndromic hearing loss that segregated with the DFNB4 locus, Pera et al. (2008) identified 24 different mutations in the SLC26A4 gene, including 8 novel mutations. The Q514K variant (605646.0030) was the most prevalent mutation, accounting for 6 (17%) of 36 mutated alleles identified in this study. </p><p>Yoon et al. (2008) performed in vitro cellular expression studies of 11 different SLC26A4 mutations (see, e.g., 605646.0004-605656.0006; 605646.0008; 605646.0011). Most of the mutations caused retention of the gene product in the intracellular region, whereas wildtype pendrin reached the plasma membrane. However, each mutant protein exhibited a different cellular localization, a different degree of N-glycosylation, and a different degree of sensitivity to rescue treatments. The H723R mutant (605646.0011) was expressed mostly in endoplasmic reticulum, and the defects could be restored somewhat by low temperature incubation. In contrast, the L236P mutant was found mainly in the centrosomal region and was temperature insensitive. Yoon et al. (2008) concluded that mutant-specific methods would be required to rescue the conformational defects of each folding mutant. </p><p>Anwar et al. (2009) analyzed the SLC26A4 gene in 46 consanguineous Pakistani families cosegregating deafness with STR markers linked to SLC26A4 and identified 16 probable pathogenic variants. Combined with earlier reported data (see Park et al., 2003), SLC26A4 mutations were identified in 56 (7.2%) of 775 Pakistani families cosegregating recessive severe to profound deafness with or without goiter, making SLC26A4 mutations the most common known cause of genetic deafness in this population. Six of the pathogenic variants were found in more than 1 family, and haplotype analysis suggested that they are founder mutations. </p><p>In 3 unrelated patients with semicircular canal dehiscence and no family history of the disorder or of deafness, Crovetto et al. (2012) excluded the 3 most common mutations in the SLC26A4 gene (605646.0005, 605646.0006, and 605646.0007). </p><p>Chattaraj et al. (2017) performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 gene in patients with EVA (600791) and only 1 detected mutant allele in the SLC26A4 gene. The authors identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on 7 of 10 mutation-negative chromosomes in a National Institutes of Health discovery cohort and 6 of 6 mutation-negative chromosomes in a Danish replication cohort was higher than the observed prevalence of 28 of 1,006 Caucasian control chromosomes (p less than 0.0001 for each EVA cohort). The corresponding heterozygous carrier rate was 28 of 503 (5.6%). The prevalence of CEVA (11 of 126) was also increased among EVA chromosomes with no mutations detected (p = 0.0042). Chattaraj et al. (2017) concluded that the CEVA haplotype causally contributes to most cases of Caucasian EVA, being present in cases where only 1 mutation is detected by traditional exonic sequencing, and possibly in some cases where no mutation has been detected. </p>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Tsukamoto et al. (2003) screened 10 Japanese families with Pendred syndrome, 32 Japanese families with bilateral sensorineural hearing loss associated with enlarged vestibular aqueduct, and 96 unrelated Japanese controls for mutations in the SLC26A4 gene. They identified causative mutations in 90% of the typical Pendred syndrome families and in 78.1% of those with sensorineural hearing loss with EVA. The same combination of mutations resulted in variable phenotypic expression (see, e.g., 605646.0011), suggesting that the 2 conditions are part of a continuous spectrum of disease. Tsukamoto et al. (2003) commented that the 3 frequent mutations accounting for nearly half of all SLC26A4 mutations in Caucasians (L236P, 605646.0005; T416P, 605646.0006; and IVS8+1G-A, 605646.0007) are rare in Japanese. The H723R mutation (605646.0011) accounted for over half of the mutations in their study, suggesting a possible founder effect. </p><p>Pryor et al. (2005) evaluated the clinical phenotype and SLC26A4 genotype of 39 patients with EVA from 31 families, definitively classifying 29 individuals. All 11 PDS patients had 2 mutant SLC26A4 alleles, whereas all 18 nonsyndromic EVA patients had either 1 or no SLC26A4 mutant alleles. Pryor et al. (2005) concluded that PDS and nonsyndromic EVA are distinct clinical and genetic entities, with PDS being a genetically homogeneous disorder caused by biallelic SLC26A4 mutations, and at least some cases of nonsyndromic EVA being associated with a single SLC26A4 mutation. They noted that the detection of a single mutant SLC26A4 allele is incompletely diagnostic without additional clinical evaluation to differentiate PDS from nonsyndromic EVA. </p><p>Napiontek et al. (2004) performed a detailed clinical and genetic study in 3 adult German sibs with typical PDS caused by the common homozygous SLC26A4 mutation T416P (605646.0006). Long-term audiologic follow-up of 23 to 25 years showed that T416P associated with a distinct type of hearing loss in each of the 3 sibs: moderate to profound progressive deafness, profound nonprogressive deafness, and a milder but more rapidly progressing deafness. Napiontek et al. (2004) concluded that these phenotypic differences were not caused by either different degrees of inner-ear malformation or sequence variations in the GJB2 gene (121011). </p><p>Although recessive mutations in SLC26A4 are known to be responsible for Pendred syndrome or nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA; 600791), a large percentage of patients with these phenotype lack mutations in the SLC26A4 coding region in one or both alleles. Yang et al. (2007) identified and characterized a key transcriptional regulatory element in the 5-prime UTR of the SLC26A4 gene that binds FOXI1 (601093), a transcriptional activator of SLC26A4. In 9 patients with Pendred syndrome or nonsyndromic EVA, a novel -103T-C mutation (605646.0027) in this regulatory element interfered with FOXI1 binding and completely abolished FOXI1-mediated transcriptional activation. Yang et al. (2007) also identified 2 Pendred and 4 EVA patients with mutations in FOXI1 that compromised its ability to activate SLC26A4 transcription; 1 of the latter EVA patients was a double heterozygote who also carried a heterozygous mutation in the SLC26A4 gene (see 605646.0028 and 601093.0001). This finding was consistent with their observation that EVA occurs in the mouse mutant doubly heterozygous for mutations in these 2 genes (Hulander et al., 2003), and the results supported a dosage-dependent model for the molecular pathogenesis of Pendred syndrome and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery. Yang et al. (2007) stated the this was the first example of digenic inheritance to be verified as a cause of human deafness. </p><p>Azaiez et al. (2007) analyzed the SLC26A4 gene in 474 patients with sensorineural hearing loss and abnormalities of the inner ear demonstrated on CT scan of the temporal bone. They detected 2 mutations in 16% of patients, 1 mutation in 19% of patients, and no mutation in 65% of patients. Comparing the distribution of SLC26A4 mutations across phenotypes, the authors found a statistically significant difference between Pendred syndrome patients and nonsyndromic EVA patients (p = 0.005) and between patients with EVA versus Mondini malformation (p = 0.0003). Pendred syndrome patients had the most severe phenotype and the most homogeneous etiology, whereas EVA patients had the least severe phenotype and the most heterogeneous etiology. For all patients, variability in the degree of hearing loss was seen across genotypes, implicating other genetic and/or environmental factors in the pathogenesis of the Pendred syndrome/Mondini/EVA disease spectrum. </p>
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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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<span class="mim-text-font">
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<p>Everett et al. (2001) generated a Pds knockout mouse. Pds -/- mice are completely deaf and also display signs of vestibular dysfunction. The inner ears appear to develop normally until embryonic day 15, after which time severe endolymphatic dilatation occurs, reminiscent of that seen radiologically in deaf individuals with PDS mutations. Additionally, in the second postnatal week severe degeneration of sensory cells and malformation of otoconia and otoconial membranes occur, as revealed by scanning electron and fluorescence confocal microscopy. No thyroid abnormality was noted in this particular mouse strain (in a 129Sv/Ev background). </p><p>Dror et al. (2010) identified a recessive mouse mutant termed 'loop' that is caused by a homozygous ser408-to-phe (S408F) substitution in a hydrophobic signature within the ninth transmembrane domain of Slc26a4. Loop/loop mice were profoundly deaf and showed abnormal vestibular behavior, such as unsteady gait, circling, absence of reaching response, and tilted body. In vitro functional expression studies in HEK293 cells showed that the S408F-mutant protein had compromised anion exchange activity, particularly of anion efflux. Detailed examination of the mutant mouse inner ear showed dramatic changes in mineral composition and size in the utricle and saccule in a differential manner. The utricles of 2-month-old wildtype mice showed thousands of small calcitic otoconia, whereas loop/loop mice had 1 giant calcitic stone. In the saccule, abnormal large stones composed of calcium oxalate formed. The differential abnormal mineralization processes between the utricle and saccule resulted from different calcium concentrations in these chambers due to different pH levels. For example, the utricle is exposed to endolymph, whereas the saccule is not. Loop/loop mice also showed deposition of ectopic stones in other components of the vestibular system. Overall, the aberrant mineralization process in mutant mice resulted in the formation of giant minerals that could no longer serve their role in proper hair cell stimulation and vestibular function. </p>
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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>31 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 PENDRED SYNDROME</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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SLC26A4, PHE667CYS
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<br />
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SNP: rs121908360,
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ClinVar: RCV000005081
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</span>
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<span class="mim-text-font">
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<p>In a family with Pendred syndrome (PDS; 274600), Everett et al. (1997) demonstrated that affected members had a homozygous T-to-G transversion in the SLC26A4 gene, predicted to cause a phe667-to-cys (F667C) amino acid substitution near the C terminus of the pendrin protein. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PENDRED SYNDROME</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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SLC26A4, 1-BP DEL, 1565G
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<br />
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SNP: rs397516417,
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gnomAD: rs397516417,
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ClinVar: RCV000036439, RCV000454189, RCV001807761, RCV001852760
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a family with Pendred syndrome (PDS; 274600), Everett et al. (1997) demonstrated that affected members had a homozygous deletion of a single G at position 1565 (1565delG) of the SLC26A4 gene, which was predicted to result either in a frameshift and premature termination of the pendrin protein or in aberrant splicing of the mRNA, or both. The deleted G is either part of or immediately adjacent to a splice donor site; thus, the precise effect of the mutation could not be predicted with certainty. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 PENDRED SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC26A4, 1-BP DEL, 1421T
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<br />
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SNP: rs397516413,
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ClinVar: RCV000036426, RCV000169097, RCV000225034, RCV000802527, RCV001291249, RCV002496558
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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 3 families with Pendred syndrome (PDS; 274600), Everett et al. (1997) found a homozygous deletion of a single T at position 1421 of the SLC26A4 gene, which was predicted to result in a frameshift and premature termination of the pendrin protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</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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SLC26A4, GLY497SER AND ILE490LEU
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<br />
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SNP: rs111033308, rs200511789,
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gnomAD: rs111033308, rs200511789,
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ClinVar: RCV000005085, RCV000036444, RCV000154348, RCV000169242, RCV000489866, RCV000673746, RCV000938882, RCV001004645, RCV001162717, RCV001375472, RCV004798754
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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 a large consanguineous Indian family with nonsyndromic autosomal recessive deafness-4 and enlarged vestibular aqueduct (DFNB4; 600791) mapping to 7q31, Li et al. (1998) identified homozygosity for 2 single-base changes in exon 13 of the SLC26A4 gene. The first was a 1713G-to-A transition, resulting in a predicted gly497-to-ser (G497S) substitution, and the second was a 1692A-to-C transversion, resulting in a predicted ile490-to-leu (I490L) substitution. The unaffected parents in all cases were heterozygous for both mutations. Both of the changes occurred within the last predicted transmembrane domain of the pendrin protein. Gly497 is 1 of only 16 strictly conserved amino acids in the entire sequence of all 15 of the closest-related sulfate transporter proteins. The G497S substitution would introduce a polar constraint inside the transmembrane domain and likely alter the conformation of protein, whereas the functional significance of the I490L substitution, if any, was less obvious. It appeared to be found only in conjunction with the G497S substitution, as neither change was detected in 184 random normal chromosomes from the same geographic area. The authors suggested that the I490L substitution may create a subtle alteration in the protein. Ten individuals ranging in age from 5 to 38 years were affected. No goiter was palpable in any of the affected individuals, and, although the perchlorate discharge test was not available, several other tests of thyroid function were normal. Axial and coronal computerized tomography of the temporal bone showed no Mondini-type cochlear malformation. </p><p>Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the G497S mutant protein was retained in the intracellular region, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity. </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 PENDRED SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC26A4, LEU236PRO
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<br />
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SNP: rs80338848,
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gnomAD: rs80338848,
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ClinVar: RCV000005086, RCV000036505, RCV000524013, RCV000824766, RCV001089560, RCV001375179, RCV004528073
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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>Both Van Hauwe et al. (1998) and Coyle et al. (1998) found a leu236-to-pro mutation (L236P) to be a frequent basis of Pendred syndrome (PDS; 274600). The amino acid substitution results from a T-to-C transition at nucleotide 707 of the SLC26A4 gene. </p><p>Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the L236P mutant protein was initially found in the endoplasmic reticulum, but later was highly concentrated at the centrosome, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity, and the defect was not corrected by lower temperature. </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>.0006 PENDRED SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC26A4, THR416PRO
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<br />
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SNP: rs28939086,
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gnomAD: rs28939086,
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ClinVar: RCV000005087, RCV000036432, RCV000435157, RCV000824771, RCV001004638, RCV004528074
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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>Both Van Hauwe et al. (1998) and Coyle et al. (1998) found that a thr416-to-pro (T416P) amino acid substitution resulting from a 1246A-C transversion in the SLC26A4 gene was a frequent finding in cases of Pendred syndrome (PDS; 274600). Van Hauwe et al. (1998) found 1 or both of the L236P (605646.0005) and T416P mutations in 9 of 14 families studied. </p><p>In 3 adult German sibs with PDS and each homozygous for the T416P mutation, Napiontek et al. (2004) noted a distinct type of hearing loss in each sib. </p><p>Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the T416P mutant protein was retained in the intracellular region, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
|
|
</div>
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</div>
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|
<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
SLC26A4, IVS8, G-A, +1
|
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|
<br />
|
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|
|
SNP: rs80338849,
|
|
|
|
|
|
gnomAD: rs80338849,
|
|
|
|
|
|
ClinVar: RCV000005088, RCV000036418, RCV000239276, RCV000477914, RCV000824768, RCV004528075
|
|
|
|
|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Coyle et al. (1998) found that a 1001+1G-A donor splice site mutation in the SLC26A4 gene was a recurrent finding in cases of Pendred syndrome (PDS; 274600). This and the L236P (605646.0005), T416P (605646.0006), and glu384-to-gly (E384G; 605646.0008) mutations accounted for 35 (74%) of PDS disease chromosomes detected by Coyle et al. (1998) and haplotype analysis favored common founders rather than mutation hotspots within the SLC26A4 gene. This donor splice site mutation was observed in 10 British families, in 5 of which descendants could be traced to the northeast of England, the region in which the family described in 1896 by Pendred resided. </p>
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|
</span>
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</div>
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<div>
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<br />
|
|
</div>
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</div>
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<div>
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|
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|
<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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SLC26A4, GLU384GLY
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<br />
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SNP: rs111033244,
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|
|
gnomAD: rs111033244,
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|
|
ClinVar: RCV000005089, RCV000036425, RCV000520205, RCV001095693, RCV002482829, RCV004528076
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In patients with Pendred syndrome (PDS; 274600), Coyle et al. (1998) identified an A-to-G change at nucleotide 1151 that resulted in a glu384-to-gly (E384G) substitution in the SLC26A4 gene. See 605646.0007. </p><p>Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the E384G mutant protein was retained in the intracellular region, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, GLY209VAL
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|
<br />
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|
|
SNP: rs111033303,
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|
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|
|
|
gnomAD: rs111033303,
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|
|
|
|
|
ClinVar: RCV000005090, RCV000036501, RCV000308471, RCV000344627, RCV000824764, RCV004528077
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 family with autosomal recessive deafness-4 and enlarged vestibular aqueduct (DFNB4; 600791) that did not fulfill the traditional criteria for Pendred syndrome (274600), Usami et al. (1999) found that 2 affected sons were homozygous for a G-to-T transversion at nucleotide 626 of the SLC26A4 gene, leading to a gly-to-val substitution at codon 209 (G209V) in the conserved region of exon 6. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, LYS369GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908361,
|
|
|
|
|
|
|
|
ClinVar: RCV000005091
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified an A-to-G transition at nucleotide 1105 of the SLC26A4 gene leading to a lys-to-glu substitution in codon 369 (K369E). The patient was compound heterozygous for the his723-to-arg mutation (H723R; 605646.0011). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PENDRED SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, HIS723ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908362,
|
|
|
|
|
|
gnomAD: rs121908362,
|
|
|
|
|
|
ClinVar: RCV000005094, RCV000005095, RCV000036477, RCV000480319, RCV001293683, RCV002476929, RCV004528078
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a 2168A-G transition in exon 19 of the SLC26A4 gene, causing a his723-to-arg (H723R) substitution. This mutation was found in homozygosity in 1 family and in compound heterozygosity in affected members of the other 2 families, who also carried a 2162C-T transition in exon 19 of the SLC26A4 gene, resulting in a thr721-to-met (T721M; 605646.0012) substitution. </p><p>Tekin et al. (2003) identified the H723R mutation in homozygous state in a Turkish patient with classic Pendred syndrome (PDS; 274600). They noted that the mutation had been identified in families from Japan and China in which affected members had sensorineural hearing loss and enlarged vestibular aqueduct without goiter. Tekin et al. (2003) suggested that the detection of the H723R mutation in Turkey reflected the migration of the Turkish people from central Asia more than 1,000 years ago. </p><p>In 2 sibs with enlarged vestibular aqueduct and an unrelated patient with Pendred syndrome, Tsukamoto et al. (2003) identified compound heterozygosity for the H723R and T721M mutations in the SLC26A4 gene, and concluded that the 2 conditions are part of a continuous spectrum of disease. </p><p>Among 26 Korean patients with DFNB4 with enlarged vestibular aqueduct (EVA), Park et al. (2005) found that the H723R mutation was the most common, accounting for 40% of the mutant alleles. </p><p>Among Chinese patients with DFNB4 with EVA, Wang et al. (2007) found that H723R was the second most common mutation, accounting for 9% of mutant alleles. </p><p>Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the H723R mutant protein was retained in the endoplasmic reticulum, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity, but the defects could be rescued considerably by decreased temperature. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PENDRED SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, THR721MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908363,
|
|
|
|
|
|
gnomAD: rs121908363,
|
|
|
|
|
|
ClinVar: RCV000005096, RCV000005097, RCV000154350, RCV001057908, RCV005041983
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the thr721-to-met (T721M) mutation in the SLC26A4 gene that was found in compound heterozygous state in patients with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791) by Usami et al. (1999), and in a patient with Pendred syndrome (PDS; 274600) by Tsukamoto et al. (2003), see 605646.0011. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, 1-BP DEL, 917T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1584317722,
|
|
|
|
|
|
|
|
ClinVar: RCV000005084
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 family with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a deletion of a single nucleotide, 917T, of the SLC26A4 gene. No mutation was found on the other allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, ALA372VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908364,
|
|
|
|
|
|
|
|
ClinVar: RCV000005092
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a C-to-T transition at nucleotide 1115 of the SLC26A4 gene, leading to an ala-to-val substitution at residue 372 (A372V). This mutation was found in compound heterozygosity with the 2111insGCTGG mutation (605646.0015) in 1 family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, 5-BP INS, NT2111
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554362735,
|
|
|
|
|
|
|
|
ClinVar: RCV000515662
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 5-bp insertion in the SLC26A4 gene (2111insGCTGG) that was found in compound heterozygous state in patients with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791) by Usami et al. (1999), see 605646.0014. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, 1-BP DEL, 279T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786204421,
|
|
|
|
|
|
gnomAD: rs786204421,
|
|
|
|
|
|
ClinVar: RCV000169009, RCV000507613, RCV001069158, RCV003474895, RCV005042348
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kopp et al. (1999) studied a consanguineous kindred from northeastern Brazil for features of Pendred syndrome (PDS; 274600). The index patient, with the classic triad of deafness, positive perchlorate test, and goiter, was found to be homozygous for a deletion of thymidine at position 279 (279delT) in exon 3 of the SLC26A4 gene, resulting in a frameshift and premature stop codon at amino acid 96. This mutation truncates the protein in its first transmembrane domain. Two other patients with deafness were homozygous for this mutation; 19 were heterozygous and 14 were homozygous for the wildtype allele. </p><p>Palos et al. (2008) noted that 279delT is a founder mutation in Galicia (northwest Spain). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, IVS4DS, A-G, +7
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs765884316,
|
|
|
|
|
|
gnomAD: rs765884316,
|
|
|
|
|
|
ClinVar: RCV000005099, RCV003155017, RCV003555919
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lopez-Bigas et al. (1999) performed mutation analysis of the individual exons of the SLC26A4 gene in a Spanish Pendred syndrome (PDS; 274600) family that showed intrafamilial variability of the deafness phenotype (2 patients with profound and 1 with moderate to severe deafness). They identified a new splice site mutation affecting intron 4 at nucleotide position 639+7. RNA analysis from lymphocytes of the affected patients showed that mutation 639+7A-G generated a new donor splice site, leading to an mRNA with an insertion of 6 nucleotides from intron 4 of SLC26A4. Since the newly created donor splice site was likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the SLC26A4 gene in the cochlea may explain the variability in the deafness presentation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, LEU445TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033307,
|
|
|
|
|
|
gnomAD: rs111033307,
|
|
|
|
|
|
ClinVar: RCV000005100, RCV000036437, RCV000413198, RCV001004641, RCV005041984
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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<p>Masmoudi et al. (2000) performed molecular analysis of the SLC26A4 gene in 2 large consanguineous families from southern Tunisia with a total of 23 individuals who had profound congenital deafness (see PDS, 274600); the same missense mutation, leu445-to-trp (L445W), was identified in all affected individuals. A widened vestibular aqueduct was found in all patients who underwent CT scan of the inner ear. In contrast, goiter was present in only 11 affected individuals; 8 of these patients who were tested had a normal result on perchlorate discharge test. </p><p>Choi et al. (2009) used in vitro functional expression studies in COS-7 cells to show that the mutant L445W protein was retained in the endoplasmic reticulum and not expressed at the cell surface, confirming its pathogenicity. </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>.0019 PENDRED SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC26A4, THR193ILE
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<br />
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SNP: rs111033348,
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gnomAD: rs111033348,
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ClinVar: RCV000005101, RCV000036499, RCV000225014, RCV000770869, RCV000824763, RCV001389159
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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 Druze family, Adato et al. (2000) found a C-to-T transition at nucleotide 801 in exon 5 of the SLC26A4 gene, predicted to result in a thr193-to-ile amino acid substitution in the protein. Members of this family were first diagnosed with recessive nonsyndromic hearing loss (Baldwin et al., 1995), i.e., DFNB4 (see 600791). Subsequent tests showed that they had goiter and therefore the diagnosis was changed to Pendred syndrome (PDS; 274600). </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>.0020 PENDRED SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC26A4, 1-BP DEL, 1197T
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<br />
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ClinVar: RCV000036426, RCV000169097, RCV000225034, RCV000802527, RCV001291249, RCV002496558
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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>Fugazzola et al. (2000) studied 3 Italian families presenting with the clinical features of Pendred syndrome (PDS; 274600). One subject, the only patient with enlargement of vestibular aqueduct and endolymphatic duct and sac at MRI, was compound heterozygous for a deletion in exon 10 of the SLC26A4 gene (1197delT) and a 1-bp insertion in exon 9 (605646.0021). The 1197delT mutation leads to a frameshift at codon 400, followed by premature termination at codon 431. </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>.0021 PENDRED SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC26A4, 1-BP INS, 2182G
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<br />
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SNP: rs1584344687,
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ClinVar: RCV000005103
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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>The second mutation in the compound heterozygous patient with Pendred syndrome (PDS; 274600) reported by Fugazzola et al. (2000) (see 605646.0020) was a single-basepair insertion in nucleotide 2182 in exon 19 (2182-2183insG), resulting in a stop codon at position 728 (tyr728 to ter; Y728X). </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>.0022 PENDRED SYNDROME</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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|
SLC26A4, IVS8, C-G, 1002-4
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<br />
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|
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SNP: rs2129315781,
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|
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ClinVar: RCV000005104, RCV003472969
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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 boy with Pendred syndrome (PDS; 274600) who presented with a solitary thyroid nodule, Massa et al. (2003) identified homozygosity for a splice site mutation (1002-4C-G) in intron 8 of the SLC26A4 gene, resulting in a putative truncated protein. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
|
</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>.0023 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SLC26A4, SER133THR
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<br />
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|
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SNP: rs121908365,
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|
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ClinVar: RCV000005105, RCV001004622, RCV001851661
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a nonconsanguineous family of Turkish origin with Pendred syndrome (PDS; 274600), Borck et al. (2003) found homozygosity for a T-to-A transversion in exon 4 of the SLC26A4 gene, which resulted in replacement of a serine residue by threonine (S133T) in the second predicted transmembrane domain of pendrin. </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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|
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, VAL138PHE
|
|
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|
<br />
|
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|
|
SNP: rs111033199,
|
|
|
|
|
|
gnomAD: rs111033199,
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|
|
|
|
|
ClinVar: RCV000005106, RCV000036493, RCV000413949, RCV000824762, RCV001375189, RCV001813952, RCV004528079
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 German families with Pendred syndrome (PDS; 274600), Borck et al. (2003) found a G-to-T transversion in exon 4 of the SLC26A4 gene resulting in a val138-to-phe (V138F) substitution in pendrin. One patient was homozygous for the mutation; the patients from the other families were compound heterozygous. Borck et al. (2003) demonstrated that V138F is a founder mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, TYR530HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033254,
|
|
|
|
|
|
gnomAD: rs111033254,
|
|
|
|
|
|
ClinVar: RCV000005107, RCV000036449, RCV001229712, RCV003472970, RCV005031392
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs from a German family with Pendred syndrome (PDS; 274600), Borck et al. (2003) demonstrated compound heterozygosity for a V138F substitution (605646.0024) and a T-to-C transition in exon 14 of the SLC26A4 gene resulting in a tyr-to-his change at residue 530 (Y530H). </p><p>Choi et al. (2009) used in vitro functional expression studies in COS-7 cells to show that the mutant Y530H protein had intracellular trafficking defects, resulting in partial retention in the endoplasmic reticulum and some post-ER locations, confirming its pathogenicity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, GLU384GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033244,
|
|
|
|
|
|
gnomAD: rs111033244,
|
|
|
|
|
|
ClinVar: RCV000005089, RCV000036425, RCV000520205, RCV001095693, RCV002482829, RCV004528076
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs from a German family with Pendred syndrome (PDS; 274600), Borck et al. (2003) demonstrated compound heterozygosity for a V138F substitution (605646.0024) and an A-to-G transition in exon 10 of the SLC26A4 gene resulting in a glu-to-gly change at residue 384 (E384G). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 PENDRED SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, -103T-C, 5-PRIME UTR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs60284988,
|
|
|
|
|
|
gnomAD: rs60284988,
|
|
|
|
|
|
ClinVar: RCV000005109, RCV000005110, RCV000154443, RCV000412985, RCV001375210, RCV004528080
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 9 patients with Pendred syndrome (PDS; 274600) or nonsyndromic autosomal deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Yang et al. (2007) identified heterozygosity for a -103T-C transition in a key regulatory element in the 5-prime UTR of the SLC26A4 gene. The mutation completely abolished transcriptional activation of the SLC26A4 gene by FOXI1 (601093). The authors stated that although they failed to identify a second SLC26A4 mutation in these families, it is not uncommon to detect a single disease-causing mutation presumably in combination with a unidentified mutation either in cis or in trans. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, GLU29GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033205,
|
|
|
|
|
|
gnomAD: rs111033205,
|
|
|
|
|
|
ClinVar: RCV000005111, RCV000036509, RCV000169251, RCV000656195, RCV001040420, RCV002496264, RCV004528081
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Yang et al. (2007) described a girl with nonsyndromic autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791) who was doubly heterozygous for a glu29-to-gln (E29Q) mutation in SLC26A4 and a gly258-to-glu (G258E) missense mutation in FOXI1 (601093.0001). The unaffected parents were each heterozygous for 1 of the mutations, respectively, and her unaffected sister carried only the E29Q mutation in SLC26A4. Yang et al. (2007) suggested that although other inheritance patterns, such as FOXI1 compound heterozygosity with a yet-to-be-identified FOXI1 mutation, could not be completely excluded, the pathogenicity of the double-heterozygous genotype was supported by several facts. First, the mouse mutant that is a double heterozygote for mutations in these 2 genes has a similar phenotype (Hulander et al., 2003). Second, the FOXI1 G258E mutation reduced transcription of SLC26A4 in vitro. Third, the SLC26A4 E29Q mutation had been reported previously in families segregating Pendred syndrome in association with other SLC26A4 mutations. Fourth, both the affected and the unaffected child had identical SLC26A4 genotypes, which was consistent with the presence of an additional genetic modifier in the affected child. Fifth, neither of these mutations had been reported in screens of 500 chromosomes. Yang et al. (2007) concluded that this was the first example of digenic inheritance to be verified as a cause of human deafness. </p><p>Pera et al. (2008) identified the E29Q variant in 1 of 214 Spanish control individuals with normal hearing. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, IVS7AS, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033313,
|
|
|
|
|
|
gnomAD: rs111033313,
|
|
|
|
|
|
ClinVar: RCV000005112, RCV000036513, RCV000169120, RCV000414330, RCV000824767, RCV001291247, RCV004737136
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Chinese patients with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Wang et al. (2007) identified an A-to-G transition in intron 7 of the SLC26A4 gene, resulting in the skipping of exon 8. This mutation was the most commonly identified, accounting for 57.6% of mutant alleles in 93 simplex families with enlarged vestibular aqueduct (EVA). </p><p>Park et al. (2005) identified the IVS7-2A-G splice site mutation in 9 (20%) of 45 mutant alleles in a study of Korean DFNB4 with EVA patients. </p><p>In 15 patients from 13 unrelated Chinese families with deafness and EVA, Hu et al. (2007) identified the IVS7-2A-G mutation in 5 (22.3%) of 22 mutant alleles. The mutation was found either in homozygosity or compound heterozygosity. Reviewing previously published studies involving Chinese patients, the authors stated that IVS7-2A-G accounted for 69.1% (76 of 110) of all mutant alleles in the Chinese, suggesting a founder effect. </p><p>Yang et al. (2009) identified double heterozygosity for this mutation in SLC26A4 (919-2A-G) and a missense mutation in the KCNJ10 gene (R348C; 602208.0009). The findings were consistent with digenic inheritance of DFNB4. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC26A4, GLN514LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908366,
|
|
|
|
|
|
|
|
ClinVar: RCV000005113, RCV001753402, RCV002476930, RCV002512793
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
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<p>In 5 of 127 Spanish probands with enlarged vestibular aqueduct and hearing loss (DFNB4; 600791), Pera et al. (2008) identified a 1541C-A transversion in exon 13 of the SLC6A4 gene, resulting in a gln514-to-lys (Q514K) substitution. The Q514K substitution was the most prevalent SLC26A4 mutation in this cohort, accounting for 6 (17%) of 36 mutated alleles. Haplotype analysis indicated a founder effect. </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>.0031 DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT, DIGENIC</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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SLC26A4, PHE335LEU
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<br />
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SNP: rs111033212,
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gnomAD: rs111033212,
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ClinVar: RCV000005114, RCV000036420, RCV000576732, RCV000656976, RCV000824769, RCV002291265
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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 with nonsyndromic hearing loss associated with enlarged vestibular aqueduct (DFNB4; 600791), Yang et al. (2009) identified double heterozygosity for a T-to-C transition at nucleotide 1003 of the SLC26A4 gene, resulting in a phe-to-leu substitution at codon 335 (F335L), and a missense mutation in the KCNJ10 gene (P194H; 602208.0008). The F335L mutation had been described by Pryor et al. (2005) and was been reported in 14 of 668 patients with enlarged vestibular aqueduct (EVA)-associated hearing loss but in none of 358 normal hearing controls, as described by Yang et al. (2009). </p><p>Choi et al. (2009) used in vitro functional expression studies in COS-7 cells to show that the mutant F335L protein was expressed normally at the cell surface and retained function in Xenopus oocytes. The authors suggested that it may not be pathogenic as a monoallelic variant. </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>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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<strong>Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus.</strong>
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Europ. J. Hum. Genet. 8: 437-442, 2000.
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Albert, S., Blons, H., Jonard, L., Feldmann, D., Chauvin, P., Loundon, N., Sergent-Allaoui, A., Houang, M., Joannard, A., Schmerber, S., Delobel, B., Leman, J., and 18 others.
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<strong>SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations.</strong>
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<strong>Mutations in the PDS gene in German families with Pendred's syndrome: V138F is a founder mutation.</strong>
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Campbell, C., Cucci, R. A., Prasad, S., Green, G. E., Edeal, J. B., Galer, C. E., Karniski, L. P., Sheffield, V. C., Smith, R. J. H.
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<strong>Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations.</strong>
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Hum. Mutat. 17: 403-411, 2001.
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Chattaraj, P., Munjal, T., Honda, K., Rendtorff, N. D., Ratay, J. S., Muskett, J. A., Risso, D. S., Roux, I., Gertz, E. M., Schaffer, A. A., Friedman, T. B., Morell, R. J., Tranebjaerg, L., Griffith, A. J.
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<strong>A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct.</strong>
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J. Med. Genet. 54: 665-673, 2017. Note: Erratum: J. Med. Genet. 55: 846 only, 2018. Erratum: J. Med. Genet. 6July, 2023. Advance Electronic Publication.
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Choi, B. Y., Stewart, A. K., Madeo, A. C., Pryor, S. P., Lenhard, S., Kittles, R., Eisenman, D., Kim, H. J., Niparko, J., Thomsen, J., Arnos, K. S., Nance, W. E., and 9 others.
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<strong>Hypo-functioning SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?</strong>
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Hum. Mutat. 30: 599-608, 2009.
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Coyle, B., Reardon, W., Herbrick, J.-A., Tsui, L.-C., Gausden, E., Lee, J., Coffey, R., Grueters, A., Grossman, A., Phelps, P. D., Luxon, L., Kendall-Taylor, P., Scherer, S. W., Trembath, R. C.
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<strong>Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre).</strong>
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Crovetto, M. A., Whyte, J., Sarasola, E., Rodriguez, J. A., Garcia-Barcina, M. J.
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<strong>Absence of COCH gene mutations in patients with superior semicircular canal dehiscence. (Letter)</strong>
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Dentice, M., Luongo, C., Elefante, A., Ambrosio, R., Salzano, S., Zannini, M., Nitsch, R., Di Lauro, R., Rossi, G., Fenzi, G., Salvatore, D.
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<strong>Pendrin is a novel in vivo downstream target gene of the TTF-1/Nkx-2.1 homeodomain transcription factor in differentiated thyroid cells.</strong>
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[Full Text: https://doi.org/10.1128/MCB.25.22.10171-10182.2005]
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Dror, A. A., Politi, Y., Shahin, H., Lenz, D. R., Dossena, S., Nofziger, C., Fuchs, H., Hrabe de Angelis, M., Paulmichl, M., Weiner, S., Avraham, K. B.
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<strong>Calcium oxalate stone formation in the inner ear as a result of an Slc26a4 mutation.</strong>
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Everett, L. A., Belyantseva, I. A., Noben-Trauth, K., Cantos, R., Chen, A., Thakkar, S. I., Hoogstraten-Miller, S. L., Kachar, B., Wu, D. K., Green, E. D.
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Everett, L. A., Glaser, B., Beck, J. C., Idol, J. R., Buchs, A., Heyman, M., Adawi, F., Hazani, E., Nassir, E., Baxevanis, A. D., Sheffield, V. C., Green, E. D.
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<strong>Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).</strong>
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Everett, L. A., Morsli, H., Wu, D. K., Green, E. D.
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<strong>Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear.</strong>
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<p class="mim-text-font">
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Fugazzola, L., Mannavola, D., Cerutti, N., Maghnie, M., Pagella, F., Bianchi, P., Weber, G., Persani, L., Beck-Peccoz, P.
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<strong>Molecular analysis of the Pendred's syndrome gene and magnetic resonance imaging studies of the inner ear are essential for the diagnosis of true Pendred's syndrome.</strong>
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[PubMed: 10902795]
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[Full Text: https://doi.org/10.1210/jcem.85.7.6694]
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<p class="mim-text-font">
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Hadj Kacem, H., Rebai, A., Kaffel, N., Masmoudi, S., Abid, M., Ayadi, H.
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<strong>PDS is a new susceptibility gene to autoimmune thyroid diseases: association and linkage study.</strong>
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<p class="mim-text-font">
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Haila, S., Hoglund, P., Scherer, S. W., Lee, J. R., Kristo, P., Coyle, B., Trembath, R., Holmberg, C., de la Chapelle, A., Kere, J.
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<strong>Genomic structure of the human congenital chloride diarrhea (CLD) gene.</strong>
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Gene 214: 87-93, 1998.
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[PubMed: 9729124]
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[Full Text: https://doi.org/10.1016/s0378-1119(98)00261-3]
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<p class="mim-text-font">
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Hu, H., Wu, L., Feng, Y., Pan, Q., Long, Z., Li, J., Dai, H., Xia, K., Liang, D., Niikawa, N., Xia, J.
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<strong>Molecular analysis of hearing loss associated with enlarged vestibular aqueduct in the mainland Chinese: a unique SLC26A4 mutation spectrum.</strong>
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J. Hum. Genet. 52: 492-497, 2007.
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[PubMed: 17443271]
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</p>
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<li>
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<p class="mim-text-font">
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Hulander, M., Kiernan, A. E., Blomqvist, S. R., Carlsson, P., Samuelsson, E. J., Johansson, B. R., Steel, K. P., Enerback, S.
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<strong>Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice.</strong>
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Development 130: 2013-2025, 2003.
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[PubMed: 12642503]
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[Full Text: https://doi.org/10.1242/dev.00376]
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</p>
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<li>
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<p class="mim-text-font">
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Kopp, P., Karamanoglu Arseven, O., Sabacan, L., Kotlar, T., Dupuis, J., Cavaliere, H., Santos, C. L. S., Jameson, J. L., Medeiros-Neto, G.
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<strong>Phenocopies for deafness and goiter development in a large inbred Brazilian kindred with Pendred's syndrome associated with a novel mutation in the PDS gene.</strong>
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J. Clin. Endocr. Metab. 84: 336-341, 1999.
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[PubMed: 9920104]
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[Full Text: https://doi.org/10.1210/jcem.84.1.5398]
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</p>
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<li>
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<p class="mim-text-font">
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Kraiem, Z., Heinrich, R., Sadeh, O., Shiloni, E., Nassir, E., Hazani, E., Glaser, B.
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<strong>Sulfate transport is not impaired in Pendred syndrome thyrocytes.</strong>
|
|
J. Clin. Endocr. Metab. 84: 2574-2576, 1999.
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[PubMed: 10404839]
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[Full Text: https://doi.org/10.1210/jcem.84.7.5973]
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</p>
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<li>
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<p class="mim-text-font">
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Li, X. C., Everett, L. A., Lalwani, A. K., Desmukh, D., Friedman, T. B., Green, E. D., Wilcox, E. R.
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<strong>A mutation in PDS causes non-syndromic recessive deafness. (Letter)</strong>
|
|
Nature Genet. 18: 215-217, 1998.
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[PubMed: 9500541]
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[Full Text: https://doi.org/10.1038/ng0398-215]
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</p>
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<li>
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<p class="mim-text-font">
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Lopez-Bigas, N., Rabionet, R., de Cid, R., Govea, N., Gasparini, P., Zelante, L., Arbones, M. L., Estivill, X.
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<strong>Splice-site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome.</strong>
|
|
Hum. Mutat. 14: 520-526, 1999.
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[PubMed: 10571950]
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Royaux, I. E., Wall, S. M., Karniski, L. P., Everett, L. A., Suzuki, K., Knepper, M. A., Green, E. D.
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<strong>Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion.</strong>
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<strong>Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).</strong>
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<strong>The Pendred syndrome gene encodes a chloride-iodide transport protein.</strong>
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Nature Genet. 21: 440-443, 1999.
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Taylor, J. P., Metcalfe, R. A., Watson, P. F., Weetman, A. P., Trembath, R. C.
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<strong>Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome.</strong>
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J. Clin. Endocr. Metab. 87: 1778-1784, 2002.
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Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J.
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Hum. Genet. 104: 188-192, 1999.
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Van Hauwe, P., Everett, L. A., Coucke, P., Scott, D. A., Kraft, M. L., Ris-Stalpers, C., Bolder, C., Otten, B., de Vijlder, J. J. M., Dietrich, N. L., Ramesh, A., Srisailapathy, S. C. R., Parving, A., Cremers, C. W. R. J., Willems, P. J., Smith, R. J. H., Green, E. D., Van Camp, G.
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Hum. Molec. Genet. 7: 1099-1104, 1998.
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Wang, Q.-J., Zhao, Y.-L., Rao, S.-Q., Guo, Y.-F., Yuan, H., Zong, L., Guan, J., Xu, B.-C., Wang, D.-Y., Han, M.-K., Lan, L., Zhai, S.-Q., Shen, Y.
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Yang, T., Gurrola, J. G., II, Wu, H., Chiu, S. M., Wangemann, P., Snyder, P. M., Smith, R. J. H.
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<strong>Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.</strong>
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Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H.
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<strong>Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).</strong>
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Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007.
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Yoon, J. S., Park, H.-J., Yoo, S.-Y., Namkung, W., Jo, M. J., Koo, S. K., Park, H.-Y., Lee, W.-S., Kim, K. H., Lee, M. G.
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<strong>Heterogeneity in the processing defect of SLC26A4 mutants.</strong>
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<p class="mim-text-font">
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Yoshida, A., Taniguchi, S., Hisatome, I., Royaux, I. E., Green, E. D., Kohn, L. D., Suzuki, K.
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<strong>Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells.</strong>
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J. Clin. Endocr. Metab. 87: 3356-3361, 2002.
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[PubMed: 12107249]
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Contributors:
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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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Ada Hamosh - updated : 03/06/2019<br>Cassandra L. Kniffin - updated : 2/16/2012<br>Cassandra L. Kniffin - updated : 1/19/2011<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Ada Hamosh - updated : 10/6/2009<br>Marla J. F. O'Neill - updated : 6/29/2009<br>Marla J. F. O'Neill - updated : 6/1/2009<br>John A. Phillips, III - updated : 5/11/2009<br>Cassandra L. Kniffin - updated : 10/6/2008<br>Cassandra L. Kniffin - updated : 8/19/2008<br>Marla J. F. O'Neill - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 10/26/2007<br>Marla J. F. O'Neill - updated : 8/9/2007<br>Victor A. McKusick - updated : 5/23/2007<br>Marla J. F. O'Neill - updated : 8/29/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>John A. Phillips, III - updated : 4/13/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>John A. Phillips, III - updated : 8/19/2004<br>Marla J. F. O'Neill - updated : 6/2/2004<br>George E. Tiller - updated : 2/4/2004<br>John A. Phillips, III - updated : 2/3/2004<br>Victor A. McKusick - updated : 1/22/2004<br>Victor A. McKusick - updated : 11/4/2003<br>John A. Phillips, III - updated : 12/4/2002<br>John A. Phillips, III - updated : 10/10/2002<br>Victor A. McKusick - updated : 6/25/2001<br>Victor A. McKusick - updated : 4/17/2001<br>George E. Tiller - updated : 3/13/2001<br>John A. Phillips, III - updated : 2/20/2001
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Victor A. McKusick : 2/14/2001
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carol : 05/08/2024<br>alopez : 02/15/2024<br>alopez : 01/26/2024<br>alopez : 01/26/2024<br>carol : 03/07/2019<br>alopez : 03/06/2019<br>carol : 10/04/2016<br>alopez : 04/23/2015<br>mcolton : 4/14/2015<br>carol : 8/30/2013<br>alopez : 6/13/2012<br>ckniffin : 6/12/2012<br>carol : 2/16/2012<br>ckniffin : 2/16/2012<br>wwang : 2/4/2011<br>ckniffin : 1/19/2011<br>alopez : 1/6/2011<br>wwang : 8/20/2010<br>ckniffin : 8/16/2010<br>wwang : 10/27/2009<br>wwang : 10/13/2009<br>alopez : 10/13/2009<br>terry : 10/6/2009<br>wwang : 7/17/2009<br>terry : 6/29/2009<br>wwang : 6/2/2009<br>terry : 6/1/2009<br>alopez : 5/11/2009<br>wwang : 10/10/2008<br>ckniffin : 10/6/2008<br>wwang : 8/28/2008<br>ckniffin : 8/19/2008<br>wwang : 3/25/2008<br>terry : 3/18/2008<br>alopez : 3/10/2008<br>wwang : 11/7/2007<br>ckniffin : 10/26/2007<br>carol : 8/22/2007<br>alopez : 8/9/2007<br>alopez : 8/9/2007<br>alopez : 5/23/2007<br>terry : 5/23/2007<br>wwang : 8/30/2006<br>terry : 8/29/2006<br>mgross : 2/3/2006<br>mgross : 2/3/2006<br>terry : 1/27/2006<br>terry : 8/3/2005<br>wwang : 5/11/2005<br>wwang : 4/13/2005<br>wwang : 3/11/2005<br>wwang : 3/8/2005<br>terry : 3/1/2005<br>alopez : 8/19/2004<br>carol : 6/8/2004<br>terry : 6/2/2004<br>carol : 3/16/2004<br>cwells : 2/4/2004<br>alopez : 2/3/2004<br>cwells : 1/23/2004<br>terry : 1/22/2004<br>tkritzer : 11/6/2003<br>terry : 11/4/2003<br>alopez : 12/4/2002<br>alopez : 10/10/2002<br>carol : 2/27/2002<br>carol : 2/27/2002<br>carol : 8/6/2001<br>alopez : 7/11/2001<br>mcapotos : 7/6/2001<br>mcapotos : 7/2/2001<br>terry : 6/25/2001<br>alopez : 4/19/2001<br>terry : 4/17/2001<br>cwells : 3/27/2001<br>cwells : 3/13/2001<br>cwells : 3/12/2001<br>alopez : 2/21/2001<br>alopez : 2/20/2001<br>alopez : 2/20/2001
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