3955 lines
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Entry
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- *603551 - HYALURONOGLUCOSAMINIDASE 2; HYAL2
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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">*603551</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603551">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000068001;t=ENST00000357750" 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=8692" 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=603551" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000068001;t=ENST00000357750" 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_003773,NM_033158,XM_005265524,XM_005265525" 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_003773" 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=603551" 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=04649&isoform_id=04649_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/HYAL2" 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/2337876,3387990,3702077,4378959,12653807,15022801,34304377,54304178,54304180,119585496,119585497,119585498,193785449,193787348,311033483,530373270,530373272,2462593397,2462593399" 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/Q12891" 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=8692" 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=ENSG00000068001;t=ENST00000357750" 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=HYAL2" 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=HYAL2" 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+8692" 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/HYAL2" 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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<div><a href="https://www.ncbi.nlm.nih.gov/gene/8692" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000357750.9&hgg_start=50317808&hgg_end=50322745&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603551[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 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=603551[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/ENSG00000068001" 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=HYAL2" 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=HYAL2" 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=HYAL2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HYAL2&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/PA29572" 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:5321" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1196334" 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/HYAL2#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:1196334" 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/8692/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=8692" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00011923;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050208-414" 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:8692" 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=HYAL2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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603551
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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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HYALURONOGLUCOSAMINIDASE 2; HYAL2
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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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LUCA2<br />
|
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HYALURONIDASE 2
|
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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=HYAL2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HYAL2</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/3/338?start=-3&limit=10&highlight=338">3p21.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:50317808-50322745&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:50,317,808-50,322,745</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<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>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/3/338?start=-3&limit=10&highlight=338">
|
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3p21.31
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Muggenthaler-Chowdhury-Chioza syndrome
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/621063"> 621063 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603551" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603551" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Hyaluronidases degrade hyaluronic acid (HA), a glycosaminoglycan present in the extracellular matrix of vertebrates. Hyaluronidase-2 exhibits very low hyaluronidase activity (<a href="#7" class="mim-tip-reference" title="Lepperdinger, G., Strobl, B., Kreil, G. <strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong> J. Biol. Chem. 273: 22466-22470, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>] [<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9712871">Lepperdinger et al., 1998</a>; <a href="#10" class="mim-tip-reference" title="Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D. <strong>Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.</strong> Proc. Nat. Acad. Sci. 98: 4443-4448, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296287[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.071572898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11296287">Rai et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11296287+9712871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By searching an EST database for sequences related to the PH-20 (<a href="/entry/600930">600930</a>) hyaluronidase, <a href="#7" class="mim-tip-reference" title="Lepperdinger, G., Strobl, B., Kreil, G. <strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong> J. Biol. Chem. 273: 22466-22470, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>] [<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9712871">Lepperdinger et al. (1998)</a> identified HYAL2 cDNAs. The HYAL2 cDNAs encode a preprotein with an N-terminal signal peptide. The predicted 452-amino acid mature protein is 36.5% identical to PH-20. Northern blot analysis indicated that HYAL2 was expressed in all human tissues tested except adult brain, and Western blot analysis detected Hyal2 protein in all mouse tissues examined except adult brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9712871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#12" class="mim-tip-reference" title="Strobl, B., Wechselberger, C., Beier, D. R., Lepperdinger, G. <strong>Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase.</strong> Genomics 53: 214-219, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790770</a>] [<a href="https://doi.org/10.1006/geno.1998.5472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790770">Strobl et al. (1998)</a> characterized Hyal2, the mouse homolog of HYAL2. The deduced proteins are 82% identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p>By RT-PCR analysis, <a href="#1" class="mim-tip-reference" title="Chow, G., Knudson, W. <strong>Characterization of promoter elements of the human HYAL-2 gene.</strong> J. Biol. Chem. 280: 26904-26912, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15923194[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.M413845200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15923194">Chow and Knudson (2005)</a> showed that HYAL2 was the predominant hyaluronidase expressed in human articular chondrocytes. RACE analysis identified multiple HYAL2 transcription initiation sites in human articular chondrocytes. Deletion analysis revealed the basal promoter for HYAL2 in chondrocytes, as well as a negative modulatory region. Luciferase reporter analysis showed that treatment of human articular chondrocytes or C-28/I2 immortalized human chondrocytes with catabolic cytokines did not alter HYAL2 expression, suggesting that HYAL2 is constitutively expressed and not inducibly regulated by catabolic agents in chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15923194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#7" class="mim-tip-reference" title="Lepperdinger, G., Strobl, B., Kreil, G. <strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong> J. Biol. Chem. 273: 22466-22470, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>] [<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9712871">Lepperdinger et al. (1998)</a> found that, unlike HYAL1 (<a href="/entry/607071">607071</a>), whose properties suggested that it was membrane associated, a fusion protein of HYAL2 and green fluorescent protein (GFP) localized to lysosomes of mammalian cells. HYAL2 hyaluronidase activity had a pH optimum below 4. Also in contrast to HYAL1, the HYAL2 enzyme hydrolyzed only HA of high molecular mass, yielding intermediate-sized HA fragments of approximately 20 kD, which were further hydrolyzed to small oligosaccharides by PH-20. The authors noted that the intermediate-sized HA fragments have specific biologic functions. <a href="#7" class="mim-tip-reference" title="Lepperdinger, G., Strobl, B., Kreil, G. <strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong> J. Biol. Chem. 273: 22466-22470, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>] [<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9712871">Lepperdinger et al. (1998)</a> concluded that HYAL2 encodes a lysosomal hyaluronidase that is present in many cell types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9712871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p><a href="#10" class="mim-tip-reference" title="Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D. <strong>Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.</strong> Proc. Nat. Acad. Sci. 98: 4443-4448, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296287[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.071572898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11296287">Rai et al. (2001)</a> and <a href="#5" class="mim-tip-reference" title="Dirks, C., Duh, F.-M., Rai, S. K., Lerman, M. I., Miller, A. D. <strong>Mechanism of cell entry and transformation by enzootic nasal tumor virus.</strong> J. Virol. 76: 2141-2149, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11836391[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/jvi.76.5.2141-2149.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836391">Dirks et al. (2002)</a> showed that HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored protein on the cell surface and serves as a receptor for entry into the cell of the jaagsiekte sheep retrovirus (JSRV). In sheep, JSRV causes a contagious form of lung cancer that arises from epithelial cells in the lower airway, including type II alveolar and bronchiolar epithelial cells. <a href="#4" class="mim-tip-reference" title="De las Heras, M., Barsky, S. H., Hasleton, P., Wagner, M., Larson, E., Egan, J., Ortin, A., Gimenez-Mas, J. A., Palmarini, M., Sharp, J. M. <strong>Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours.</strong> Europ. Resp. J. 16: 330-332, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10968511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10968511</a>] [<a href="https://doi.org/10.1034/j.1399-3003.2000.16b23.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10968511">De las Heras et al. (2000)</a> reported that antiserum directed against the JSRV capsid protein crossreacted with 30% of human pulmonary adenocarcinoma samples but not with normal lung tissue or adenocarcinomas from other tissues. These findings supported the possibility of a viral etiology of some human lung cancers, particularly the bronchioloalveolar adenocarcinoma type, which is morphologically very similar to the sheep tumors. The viral envelope (Env) protein alone can transform cultured cells, and <a href="#3" class="mim-tip-reference" title="Danilkovitch-Miagkova, A., Duh, F.-M., Kuzmin, I., Angeloni, D., Liu, S.-L., Miller, A. D., Lerman, M. I. <strong>Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.</strong> Proc. Nat. Acad. Sci. 100: 4580-4585, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676986</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12676986[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.0837136100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676986">Danilkovitch-Miagkova et al. (2003)</a> hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. They showed that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase, also called macrophage stimulating-1 receptor (MST1R; <a href="/entry/600168">600168</a>), rendering it functionally silent. In human cells expressing a JSRV Env transgene, the Env protein physically associated with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the AKT1 (<a href="/entry/164730">164730</a>) and mitogen-activated protein kinase-1 (MAPK1; <a href="/entry/176948">176948</a>) pathways, leading to oncogenic transformation of immortalized human bronchial epithelial cells. <a href="#3" class="mim-tip-reference" title="Danilkovitch-Miagkova, A., Duh, F.-M., Kuzmin, I., Angeloni, D., Liu, S.-L., Miller, A. D., Lerman, M. I. <strong>Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.</strong> Proc. Nat. Acad. Sci. 100: 4580-4585, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676986</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12676986[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.0837136100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12676986">Danilkovitch-Miagkova et al. (2003)</a> demonstrated activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12676986+11836391+10968511+11296287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#8" class="mim-tip-reference" title="Miller, A. D. <strong>Personal Communication.</strong> Seattle, Wash. 12/10/2002."None>Miller (2002)</a> provided an explanation for the discrepancy between the conclusions of <a href="#7" class="mim-tip-reference" title="Lepperdinger, G., Strobl, B., Kreil, G. <strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong> J. Biol. Chem. 273: 22466-22470, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>] [<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9712871">Lepperdinger et al. (1998)</a> and <a href="#10" class="mim-tip-reference" title="Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D. <strong>Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.</strong> Proc. Nat. Acad. Sci. 98: 4443-4448, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296287[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.071572898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11296287">Rai et al. (2001)</a>, the former that HYAL2 is a lysosomal enzyme and the latter that it is a cell surface enzyme. <a href="#7" class="mim-tip-reference" title="Lepperdinger, G., Strobl, B., Kreil, G. <strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong> J. Biol. Chem. 273: 22466-22470, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>] [<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9712871">Lepperdinger et al. (1998)</a> linked GFP to the carboxy end of HYAL2 and found GFP in the lysosome, leading to the conclusion that HYAL2 is also in the lysosome. The findings of <a href="#10" class="mim-tip-reference" title="Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D. <strong>Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.</strong> Proc. Nat. Acad. Sci. 98: 4443-4448, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296287[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.071572898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11296287">Rai et al. (2001)</a> that HYAL2 is a GPI-anchored protein on the cell surface showed that GFP would likely be cleaved from HYAL2 during GPI addition, leaving HYAL2 on the cell surface and resulting in GFP transit to the lysosome for degradation. <a href="#10" class="mim-tip-reference" title="Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D. <strong>Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.</strong> Proc. Nat. Acad. Sci. 98: 4443-4448, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296287[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.071572898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11296287">Rai et al. (2001)</a> also showed that HYAL2 has very low hyaluronidase activity, if any, compared to serum hyaluronidase HYAL1, and that HYAL2 serves as a receptor for JSRV. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11296287+9712871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using hyaluronan as substrate, <a href="#14" class="mim-tip-reference" title="Vigdorovich, V., Miller, A. D., Strong, R. K. <strong>Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus.</strong> J. Virol. 81: 3124-3129, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17229709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17229709</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17229709[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/JVI.02177-06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17229709">Vigdorovich et al. (2007)</a> demonstrated that recombinant soluble HYAL2 had hyaluronidase activity, with a sharp pH optimum of 5.6. Mutation analysis showed that hyaluronidase activity was not required for HYAL2 to function as JSRV receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17229709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#12" class="mim-tip-reference" title="Strobl, B., Wechselberger, C., Beier, D. R., Lepperdinger, G. <strong>Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase.</strong> Genomics 53: 214-219, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790770</a>] [<a href="https://doi.org/10.1006/geno.1998.5472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790770">Strobl et al. (1998)</a> found that the human and mouse HYAL2 genes contain 4 exons and have the same exon-intron organization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#7" class="mim-tip-reference" title="Lepperdinger, G., Strobl, B., Kreil, G. <strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong> J. Biol. Chem. 273: 22466-22470, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>] [<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9712871">Lepperdinger et al. (1998)</a> stated that the HYAL2 gene is identical to LUCA2, which <a href="#15" class="mim-tip-reference" title="Wei, M.-H., Latif, F., Bader, S., Kashuba, V., Chen, J.-Y., Duh, F.-M., Sekido, Y., Lee, C.-C., Geil, L., Kuzmin, I., Zabarovsky, E., Klein, G., Zbar, B., Minna, J. D., Lerman, M. I. <strong>Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG.</strong> Cancer Res. 56: 1487-1492, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8603390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8603390</a>]" pmid="8603390">Wei et al. (1996)</a> positioned on a contig of human chromosome 3p21.3, a region frequently deleted in lung cancer (see <a href="/entry/182280">182280</a>). <a href="#15" class="mim-tip-reference" title="Wei, M.-H., Latif, F., Bader, S., Kashuba, V., Chen, J.-Y., Duh, F.-M., Sekido, Y., Lee, C.-C., Geil, L., Kuzmin, I., Zabarovsky, E., Klein, G., Zbar, B., Minna, J. D., Lerman, M. I. <strong>Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG.</strong> Cancer Res. 56: 1487-1492, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8603390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8603390</a>]" pmid="8603390">Wei et al. (1996)</a> observed that LUCA2 is located near LUCA1 (HYAL1; <a href="/entry/607071">607071</a>). By analysis of an interspecific backcross, <a href="#12" class="mim-tip-reference" title="Strobl, B., Wechselberger, C., Beier, D. R., Lepperdinger, G. <strong>Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase.</strong> Genomics 53: 214-219, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790770</a>] [<a href="https://doi.org/10.1006/geno.1998.5472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790770">Strobl et al. (1998)</a> mapped the Hyal2 gene to mouse chromosome 9 in a region showing homology of synteny with human 3p21. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9790770+8603390+9712871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p>In a cohort of 33 consanguineous families with facial dysmorphism and/or skeletal dysplasia, <a href="#11" class="mim-tip-reference" title="Shaheen, R., Patel, N., Shamseldin, H., Alzahrani, F., Al-Yamany, R., ALMoisheer, A., Ewida, N., Anazi, S., Alnemer, M., Elsheikh, M., Alfaleh, K., Alshammari, M., and 13 others. <strong>Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.</strong> Genet. Med. 18: 686-695, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26633546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26633546</a>] [<a href="https://doi.org/10.1038/gim.2015.147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26633546">Shaheen et al. (2016)</a> performed autozygome analysis and whole-exome/genome sequencing and identified 2 affected members of a multiply consanguineous Saudi family with Muggenthaler-Chowdhury-Chioza syndrome (MCCS; <a href="/entry/621063">621063</a>), characterized by frontonasal dysplasia and high myopia, who were homozygous for a missense mutation in the HYAL2 gene (P250L; <a href="#0001">603551.0001</a>). Sanger sequencing validated the mutation and its segregation with disease in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26633546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By whole-exome sequencing in an extended Amish pedigree in which 5 children had frontonasal dysplasia and myopia mapping to chromosome 3p21, <a href="#9" class="mim-tip-reference" title="Muggenthaler, M. M. A., Chowdhury, B., Hasan, S. N., Cross, H. E., Mark, B., Harlalka, G. V., Patton, M. A., Ishida, M., Behr, E. R., Sharma, S., Zahka, K., Faqeih, E., and 12 others. <strong>Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice.</strong> PLoS Genet. 13: e1006470, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28081210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28081210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28081210[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/10.1371/journal.pgen.1006470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28081210">Muggenthaler et al. (2017)</a> identified homozygosity for a missense mutation in the HYAL2 gene (K148R; <a href="#0002">603551.0002</a>) that segregated with disease and was not found in public variant databases. However, it was identified in heterozygosity in 7 of 266 Amish controls, indicating an allele frequency of 0.013 in the Amish population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28081210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 10 patients from 6 families with frontonasal dysplasia and myopia, with or without congenital cardiac malformations and cleft lip/palate, <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a> identified homozygosity or compound heterozygosity for mutations in the HYAL2 gene (see, e.g., <a href="#0002">603551.0002</a>-<a href="#0010">603551.0010</a>). The mutations segregated with disease in the respective families, and were either not found or were rare in the gnomAD database. Functional analysis in transfected cells showed reduced or absent HYAL2 protein, and cell surface expression of the mutants was absent or present at low levels compared to wildtype HYAL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p>Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats, with significant animal health and economic consequences. The host range of JSRV is in part limited by species-specific differences in the virus entry receptor, hyaluronidase-2 (Hyal2), which is not functional as a receptor in mice but is functional in humans. Sheep are immunotolerant of JSRV because of expression of closely related endogenous retroviruses, which are not present in humans and most other species, and that may facilitate oncogenesis. Using a replication-incompetent adeno-associated virus vector, <a href="#16" class="mim-tip-reference" title="Wootton, S. K., Halbert, C. L., Miller, A. D. <strong>Sheep retrovirus structural protein induces lung tumours.</strong> Nature 434: 904-907, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15829964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829964">Wootton et al. (2005)</a> showed that expression of the JSRV envelope (Env) protein alone in lungs of mice results in tumors with a bronchioloalveolar localization like those seen in sheep. Whereas lethal disease was observed in immunodeficient mice, tumor development was almost entirely blocked in immunocompetent mice. <a href="#16" class="mim-tip-reference" title="Wootton, S. K., Halbert, C. L., Miller, A. D. <strong>Sheep retrovirus structural protein induces lung tumours.</strong> Nature 434: 904-907, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15829964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829964">Wootton et al. (2005)</a> concluded that their results provided a rare example of an oncogenic viral structural protein, showed that interaction of the viral Env protein with the virus entry receptor Hyal2 is not required for tumorigenesis, and indicated that immune recognition of Env can protect against JSRV tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15829964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum life span exceeding 30 years. In addition, it is unusually resistant to cancer. <a href="#13" class="mim-tip-reference" title="Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V., Seluanov, A. <strong>High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat.</strong> Nature 499: 346-349, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23783513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23783513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23783513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23783513">Tian et al. (2013)</a> identified a mechanism responsible for the cancer resistance. <a href="#13" class="mim-tip-reference" title="Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V., Seluanov, A. <strong>High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat.</strong> Nature 499: 346-349, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23783513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23783513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23783513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23783513">Tian et al. (2013)</a> found that naked mole rat fibroblasts secrete extremely high molecular mass hyaluronan (HA), which is over 5 times larger than human or mouse HA. This high molecular mass HA accumulates abundantly in naked mole rat tissues owing to the decreased activity of HA-degrading enzymes and a species-specific sequence of hyaluronan synthase-2 (HAS2; <a href="/entry/601636">601636</a>). Furthermore, the naked mole rat cells are more sensitive to HA signaling, as they have a higher affinity to HA compared to mouse or human cells. Perturbation of the signaling pathways sufficient for malignant transformation of mouse fibroblasts failed to transform naked mole rat cells. However, once high molecular mass HA was removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme HYAL2, naked mole rat cells became susceptible to malignant transformation and readily formed tumors in mice. <a href="#13" class="mim-tip-reference" title="Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V., Seluanov, A. <strong>High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat.</strong> Nature 499: 346-349, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23783513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23783513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23783513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23783513">Tian et al. (2013)</a> speculated that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels and that this trait may have then been coopted to provide cancer resistance and longevity to this species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23783513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p><a href="#2" class="mim-tip-reference" title="Chowdhury, B., Hemming, R., Hombach-Klonisch, S., Flamion, B., Triggs-Raine, B. <strong>Murine hyaluronidase 2 deficiency results in extracellular hyaluronan accumulation and severe cardiopulmonary dysfunction.</strong> J. Biol. Chem. 288: 520-528, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23172227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23172227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23172227[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.M112.393629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23172227">Chowdhury et al. (2013)</a> found that Hyal2 -/- mice suffered from preweaning lethality, with only 9% of mice being Hyal2 -/- at weaning rather than the expected 25%. Of the viable Hyal2 -/- mice, 54% were smaller than littermates and exhibited rapid-onset lethargy, weight loss, dull coat, shortness of breath, and dilated left or right atrium, which the authors defined as the acute group. The remaining 46% developed slower onset of lethargy, loss of weight, and poor grooming, but not severe atrial dilation, which the authors defined as the nonacute group. About 43% of Hyal2 -/- mice were missing 1 kidney, but kidney loss was independent of atrial dilation and was not studied further. Both acute and nonacute groups displayed heart valve expansion, with accumulation of hyaluronan, altering the structure and organization of valves. The acute group had changes in heart structure in the upper ventricular region, close to the base of the heart. Both groups exhibited cardiac hypertrophy with an accumulation of extracellular matrix. Severe pulmonary fibrosis was observed in the acute group, but not in the nonacute group. Increased hyaluronan levels and size were seen in sera and hearts of both groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23172227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p><a href="#9" class="mim-tip-reference" title="Muggenthaler, M. M. A., Chowdhury, B., Hasan, S. N., Cross, H. E., Mark, B., Harlalka, G. V., Patton, M. A., Ishida, M., Behr, E. R., Sharma, S., Zahka, K., Faqeih, E., and 12 others. <strong>Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice.</strong> PLoS Genet. 13: e1006470, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28081210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28081210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28081210[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/10.1371/journal.pgen.1006470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28081210">Muggenthaler et al. (2017)</a> performed micro-CT studies of Hyal2 -/- mouse pups and observed an underdeveloped and underossified viscerocranium compared to littermate controls. Several central palate bones were underdeveloped, the vomer did not fuse centrally or form a head that articulated with the maxilla, and the ethmoid bone was nearly absent. Dissecting microscopy of the palates of Hyal2 -/- embryos from E18.5 to E19.5 revealed partial clefts and/or shortening of the secondary palate as well as abnormally formed rugae. Micro-CT confirmed reduced ossification and underdevelopment of the viscerocranial bones, particularly the vomer, consistent with submucosal cleft palate. The authors noted that this palatal malformation and clefting are likely to contribute significantly to the observed preweaning lethality in Hyal2-null mice. Histologic studies of P1 mice confirmed that the viscerocranial bones of all Hyal2 -/- mice were underdeveloped, and coronal sections showed the failed fusion between the epithelial surface of the vomeronasal organ and the dorsal side of the palate shelf. Hyaluronan levels were clearly increased in Hyal2-deficient tissues. The authors also noted that cor triatriatum sinister, a rare cardiac anomaly present in 1 of 7 human patients with HYAL2 mutations, had been detected in 50% of Hyal2 -/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28081210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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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> rs781999115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs781999115;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/rs781999115?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=rs781999115" 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=rs781999115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In a niece and her maternal aunt (cases 14DG1221 and 15DG1187) from a large multiply consanguineous Saudi family (family 11) with Muggenthaler-Chowdhury-Chioza syndrome (MCCS; <a href="/entry/621063">621063</a>), characterized by frontonasal dysplasia and high myopia, <a href="#11" class="mim-tip-reference" title="Shaheen, R., Patel, N., Shamseldin, H., Alzahrani, F., Al-Yamany, R., ALMoisheer, A., Ewida, N., Anazi, S., Alnemer, M., Elsheikh, M., Alfaleh, K., Alshammari, M., and 13 others. <strong>Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.</strong> Genet. Med. 18: 686-695, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26633546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26633546</a>] [<a href="https://doi.org/10.1038/gim.2015.147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26633546">Shaheen et al. (2016)</a> identified homozygosity for a c.749C-T transition (c.749C-T, NM_033158.4) in the HYAL2 gene, resulting in a pro250-to-leu (P250L) substitution. Sanger sequencing confirmed the mutation and its segregation with disease in the pedigree. Both affected individuals had hypertelorism, broad nose, and micrognathia, and 1 had bilateral cleft lip and palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26633546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Muggenthaler, M. M. A., Chowdhury, B., Hasan, S. N., Cross, H. E., Mark, B., Harlalka, G. V., Patton, M. A., Ishida, M., Behr, E. R., Sharma, S., Zahka, K., Faqeih, E., and 12 others. <strong>Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice.</strong> PLoS Genet. 13: e1006470, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28081210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28081210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28081210[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/10.1371/journal.pgen.1006470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28081210">Muggenthaler et al. (2017)</a> restudied this family (designated family 2) and noted that the P250L variant was absent in 817 ethnically matched controls and was not found in the Exome Variant Server or 1000 Genomes Project databases; however, it was present in 2 carriers in the ExAC database. Western blot analysis of transiently transfected mouse embryonic fibroblasts demonstrated a 20-fold reduction in protein level of the mutant compared to wildtype HYAL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28081210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1321268291 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1321268291;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=rs1321268291" 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=rs1321268291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In 5 affected children from a large Amish pedigree (family 1) with myopia and craniofacial dysmorphisms including hypertelorism, broad nose, and bilateral cleft lip and palate (MCCS; <a href="/entry/621063">621063</a>), <a href="#9" class="mim-tip-reference" title="Muggenthaler, M. M. A., Chowdhury, B., Hasan, S. N., Cross, H. E., Mark, B., Harlalka, G. V., Patton, M. A., Ishida, M., Behr, E. R., Sharma, S., Zahka, K., Faqeih, E., and 12 others. <strong>Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice.</strong> PLoS Genet. 13: e1006470, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28081210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28081210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28081210[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/10.1371/journal.pgen.1006470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28081210">Muggenthaler et al. (2017)</a> identified homozygosity for a c.443A-G transition (c.443A-G, NM_003773.4) in the HYAL2 gene, resulting in a lys148-to-arg (K148R) substitution. Sanger sequencing validated the mutation and its segregation with disease in the family. The variant was not found in the Exome Variant Server ESP, 1000 Genomes Project, or ExAC databases; however, it was identified in heterozygosity in 7 of 266 Amish controls, indicating an allele frequency of 0.013 in the Amish population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28081210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a> reported an Ohio Amish sister and brother (patients 1 and 2) with MCCS who were distant relatives of the Amish pedigree described by <a href="#9" class="mim-tip-reference" title="Muggenthaler, M. M. A., Chowdhury, B., Hasan, S. N., Cross, H. E., Mark, B., Harlalka, G. V., Patton, M. A., Ishida, M., Behr, E. R., Sharma, S., Zahka, K., Faqeih, E., and 12 others. <strong>Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice.</strong> PLoS Genet. 13: e1006470, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28081210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28081210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28081210[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/10.1371/journal.pgen.1006470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28081210">Muggenthaler et al. (2017)</a> and were homozygous for the same K148R founder variant in the HYAL2 gene. The mutation, which segregated with disease in the family, had an allele frequency of 0.6% in the Anabaptist variant server. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28081210+34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>In a 19-year-old Italian man (patient 3) with frontonasal dysplasia and severe myopia, who also exhibited coarctation of the aorta, ventricular septal defect, and pectus excavatum (MCCS; <a href="/entry/621063">621063</a>), <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a> identified compound heterozygosity for a c.829C-T transition (c.829C-T, NM_003773.4) in the HYAL2 gene, resulting in an arg277-to-cys (R277C) substitution at a highly conserved residue, and a c.883C-T transition, resulting in an arg295-to-ter (R295X) substitution. The mutations segregated with disease in the family, and both were present at low minor allele frequency in the gnomAD database (v.2.1.1; v3.1.1), only in heterozygosity. Analysis of transiently transfected mouse embryonic fibroblasts showed no detectable HYAL2 protein with the R295X mutant, whereas the R277C mutant showed very low protein levels, suggesting accelerated degradation. Immunofluorescence analysis of transfected cells showed no intracellular or cell surface expression with the R295X mutant, and no cell surface expression with the R277C mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0004 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</div></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> rs782682203 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs782682203;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/rs782682203?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=rs782682203" 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=rs782682203" 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=RCV001731162 OR RCV005002010" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001731162, RCV005002010" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001731162...</a>
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<div class="mim-changed mim-change"><p>For discussion of the c.883C-T transition (c.883C-T, NM_003773.4) in the HYAL2 gene, resulting in an arg295-to-ter (R295X) substitution, that was found in compound heterozygous state in a 19-year-old Italian man (patient 3) with frontonasal dysplasia and severe myopia (MCCS; <a href="/entry/621063">621063</a>) by <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a>, see <a href="#0003">603551.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0005 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</div></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">rs1553716439 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553716439;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=rs1553716439" 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=rs1553716439" 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=RCV001731156 OR RCV005002005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001731156, RCV005002005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001731156...</a>
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<div class="mim-changed mim-change"><p>In 2 sibs (patients 4 and 5) of North European ancestry, who died at ages 10 months and 10 days with frontonasal dysplasia, myopia, and congenital cardiac malformations (MCCS; <a href="/entry/621063">621063</a>), <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a> identified compound heterozygosity for a c.194C-G transversion (c.194C-G, NM_003773.4) in exon 2 of the HYAL2 gene, resulting in a ser65-to-ter (S65X) substitution, and a c.1273T-G transversion, resulting in a phe425-to-val (F425V) substitution at a highly conserved residue. The mutations segregated with disease in the family. The S65X variant was not found in the gnomAD database (v2.1.1; v3.1.1), whereas the F425V variant was present at low minor allele frequency, only in heterozygosity. Analysis of transiently transfected mouse embryonic fibroblasts showed no detectable HYAL2 protein with the S65X mutant, whereas the F425V mutant showed very low protein levels, suggesting accelerated degradation. Immunofluorescence analysis of transfected cells showed no intracellular or cell surface HYAL2 with either mutant. One sib died of complications of pulmonary hypertension, and the other sib died due to complex cardiovascular anomalies, including mitral valve atresia, hypoplastic left ventricle, double outlet right ventricle with pulmonary valve atresia, and hypoplastic pulmonary and aortoplumonary arteries with agenesis of the ductus venosus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0006 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</div></strong>
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<div class="mim-changed mim-change"><p>For discussion of the c.1237T-G transversion (c.1237T-G, NM_003773.4) in the HYAL2 gene, resulting in a phe425-to-val (F425V) substitution, that was found in compound heterozygous state in 2 sibs (patients 4 and 5) with frontonasal dysplasia and myopia (MCCS; <a href="/entry/621063">621063</a>) by <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a>, see <a href="#0005">603551.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0007 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</div></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">rs2109322411 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2109322411;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=rs2109322411" 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=rs2109322411" 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=RCV001731164 OR RCV005002012" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001731164, RCV005002012" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001731164...</a>
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<div class="mim-changed mim-change"><p>In a 4-year-old German boy (patient 7) with frontonasal dysplasia, high myopia, tetralogy of Fallot, and cleft lip and palate (MCCS; <a href="/entry/621063">621063</a>), <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a> identified compound heterozygosity for a 2-bp deletion (c.1271_1272delAC, NM_003773.4) in the HYAL2 gene, causing a frameshift predicted to result in a premature termination codon (His424LeufsTer12) within the final exon, and a c.713T-G transversion, resulting in a leu238-to-arg (L238R) substitution at a highly conserved residue. The mutations segregated with disease in the family and were not found in the gnomAD database. Analysis of transiently transfected mouse embryonic fibroblasts showed very low protein levels with the L238R mutant, suggesting accelerated degradation, whereas the His424LeufsTer12 variant was present at levels similar to wildtype HYAL2. Immunofluorescence analysis of transfected cells showed no intracellular or cell surface expression with the truncated variant, but a low level of cell surface expression was detected for the L238R mutant compared to wildtype HYAL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0008 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</div></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">rs2109324483 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2109324483;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=rs2109324483" 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=rs2109324483" 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=RCV001731159 OR RCV005002007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001731159, RCV005002007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001731159...</a>
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<div class="mim-changed mim-change"><p>For discussion of the c.713T-G transversion (c.713T-G, NM_003773.4) in the HYAL2 gene, resulting in a leu238-to-arg (L238R) substitution, that was found in compound heterozygous state in a 4-year-old German boy (patient 7) with frontonasal dysplasia and high myopia (MCCS; <a href="/entry/621063">621063</a>) by <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a>, see <a href="#0007">603551.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0009 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</div></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">rs1553715895 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553715895;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=rs1553715895" 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=rs1553715895" 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=RCV001731163 OR RCV005002011" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001731163, RCV005002011" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001731163...</a>
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<div class="mim-changed mim-change"><p>In 3 Polish sibs (patients 8, 9, and 10) with frontonasal dysplasia, myopia, and significant cardiac malformations, including tetralogy of Fallot, hypoplastic left heart, and double-outlet right ventricle (MCCS; <a href="/entry/621063">621063</a>), <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a> identified compound heterozygosity for missense mutations at highly conserved residues: a c.1132C-T transition (c.1132C-T, NM_003773.4) in the HYAL2 gene, resulting in an arg378-to-cys (R378C) substitution, and a c.190G-A transition, resulting in an ala64-to-thr (A64T) substitution. The mutations, which segregated with disease in the family, were both present at low minor allele frequency in the gnomAD database (v2.1.1; v3.1.1), only in heterozygosity. Due to the impact of the COVID pandemic, no functional work could be performed on these HYAL2 variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<strong><div class="mim-changed mim-change">.0010 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</div></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">rs782642246 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs782642246;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=rs782642246" 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=rs782642246" 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=RCV001731155 OR RCV005002004" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001731155, RCV005002004" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001731155...</a>
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>For discussion of the c.190G-A transition (c.190G-A, NM_003773.4) in the HYAL2 gene, resulting in an ala64-to-thr (A64T) substitution, that was found in compound heterozygous state in 3 Polish sibs (patients 8, 9, and 10) with frontonasal dysplasia and myopia (MCCS; <a href="/entry/621063">621063</a>) by <a href="#6" class="mim-tip-reference" title="Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others. <strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong> Genet. Med. 24: 631-644, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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.gim.2021.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34906488">Fasham et al. (2022)</a>, see <a href="#0009">603551.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34906488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="Chow2005" class="mim-anchor"></a>
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Chow, G., Knudson, W.
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<strong>Characterization of promoter elements of the human HYAL-2 gene.</strong>
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J. Biol. Chem. 280: 26904-26912, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15923194[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=15923194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M413845200" target="_blank">Full Text</a>]
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Chowdhury, B., Hemming, R., Hombach-Klonisch, S., Flamion, B., Triggs-Raine, B.
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<strong>Murine hyaluronidase 2 deficiency results in extracellular hyaluronan accumulation and severe cardiopulmonary dysfunction.</strong>
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J. Biol. Chem. 288: 520-528, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23172227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23172227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23172227[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=23172227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M112.393629" target="_blank">Full Text</a>]
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<a id="Danilkovitch-Miagkova2003" class="mim-anchor"></a>
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Danilkovitch-Miagkova, A., Duh, F.-M., Kuzmin, I., Angeloni, D., Liu, S.-L., Miller, A. D., Lerman, M. I.
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<strong>Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.</strong>
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Proc. Nat. Acad. Sci. 100: 4580-4585, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12676986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12676986</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12676986[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=12676986" 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.0837136100" target="_blank">Full Text</a>]
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De las Heras, M., Barsky, S. H., Hasleton, P., Wagner, M., Larson, E., Egan, J., Ortin, A., Gimenez-Mas, J. A., Palmarini, M., Sharp, J. M.
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<strong>Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours.</strong>
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Europ. Resp. J. 16: 330-332, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10968511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10968511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10968511" 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.1399-3003.2000.16b23.x" target="_blank">Full Text</a>]
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Dirks, C., Duh, F.-M., Rai, S. K., Lerman, M. I., Miller, A. D.
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<strong>Mechanism of cell entry and transformation by enzootic nasal tumor virus.</strong>
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J. Virol. 76: 2141-2149, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11836391[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=11836391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/jvi.76.5.2141-2149.2002" target="_blank">Full Text</a>]
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Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others.
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<strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong>
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Genet. Med. 24: 631-644, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34906488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34906488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34906488[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=34906488" 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.gim.2021.10.014" target="_blank">Full Text</a>]
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<a id="Lepperdinger1998" class="mim-anchor"></a>
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Lepperdinger, G., Strobl, B., Kreil, G.
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<strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong>
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J. Biol. Chem. 273: 22466-22470, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9712871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9712871</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9712871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.35.22466" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Miller2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Miller, A. D.
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<strong>Personal Communication.</strong>
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|
Seattle, Wash. 12/10/2002.
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</p>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Muggenthaler2017" class="mim-anchor"></a>
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<div class="mim-changed mim-change">
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<p class="mim-text-font">
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Muggenthaler, M. M. A., Chowdhury, B., Hasan, S. N., Cross, H. E., Mark, B., Harlalka, G. V., Patton, M. A., Ishida, M., Behr, E. R., Sharma, S., Zahka, K., Faqeih, E., and 12 others.
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<strong>Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice.</strong>
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PLoS Genet. 13: e1006470, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28081210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28081210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28081210[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=28081210" 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/10.1371/journal.pgen.1006470" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Rai2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D.
|
|
<strong>Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.</strong>
|
|
Proc. Nat. Acad. Sci. 98: 4443-4448, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296287[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=11296287" 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.071572898" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Shaheen2016" class="mim-anchor"></a>
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<div class="mim-changed mim-change">
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<p class="mim-text-font">
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Shaheen, R., Patel, N., Shamseldin, H., Alzahrani, F., Al-Yamany, R., ALMoisheer, A., Ewida, N., Anazi, S., Alnemer, M., Elsheikh, M., Alfaleh, K., Alshammari, M., and 13 others.
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<strong>Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.</strong>
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Genet. Med. 18: 686-695, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26633546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26633546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26633546" 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/gim.2015.147" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Strobl1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Strobl, B., Wechselberger, C., Beier, D. R., Lepperdinger, G.
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<strong>Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase.</strong>
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Genomics 53: 214-219, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1998.5472" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Tian2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V., Seluanov, A.
|
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<strong>High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat.</strong>
|
|
Nature 499: 346-349, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23783513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23783513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23783513[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=23783513" 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/nature12234" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Vigdorovich2007" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Vigdorovich, V., Miller, A. D., Strong, R. K.
|
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<strong>Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus.</strong>
|
|
J. Virol. 81: 3124-3129, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17229709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17229709</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17229709[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=17229709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/JVI.02177-06" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Wei1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wei, M.-H., Latif, F., Bader, S., Kashuba, V., Chen, J.-Y., Duh, F.-M., Sekido, Y., Lee, C.-C., Geil, L., Kuzmin, I., Zabarovsky, E., Klein, G., Zbar, B., Minna, J. D., Lerman, M. I.
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<strong>Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG.</strong>
|
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Cancer Res. 56: 1487-1492, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8603390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8603390</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8603390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Wootton2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wootton, S. K., Halbert, C. L., Miller, A. D.
|
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<strong>Sheep retrovirus structural protein induces lung tumours.</strong>
|
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Nature 434: 904-907, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15829964[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=15829964" 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/nature03492" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/15/2025
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</span>
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</div>
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</div>
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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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Bao Lige - updated : 01/08/2025<br>Ada Hamosh - updated : 9/20/2013<br>Patricia A. Hartz - updated : 6/5/2007<br>Ada Hamosh - updated : 9/19/2005<br>Victor A. McKusick - updated : 6/6/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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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Rebekah S. Rasooly : 2/18/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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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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alopez : 01/15/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/10/2025<br>mgross : 01/08/2025<br>alopez : 11/06/2019<br>alopez : 04/10/2018<br>carol : 01/28/2014<br>alopez : 9/20/2013<br>terry : 4/2/2010<br>mgross : 6/21/2007<br>terry : 6/5/2007<br>alopez : 9/20/2005<br>terry : 9/19/2005<br>alopez : 9/23/2004<br>tkritzer : 10/15/2003<br>tkritzer : 6/13/2003<br>terry : 6/6/2003<br>mgross : 6/26/2002<br>mgross : 7/16/1999<br>terry : 7/14/1999<br>psherman : 2/18/1999
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603551
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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HYALURONOGLUCOSAMINIDASE 2; HYAL2
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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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<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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LUCA2<br />
|
|
HYALURONIDASE 2
|
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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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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: HYAL2</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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<p>
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<span class="mim-text-font">
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<strong>
|
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<em>
|
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Cytogenetic location: 3p21.31
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 3:50,317,808-50,322,745 </span>
|
|
</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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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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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
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<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
3p21.31
|
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</span>
|
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</td>
|
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|
|
<td>
|
|
<span class="mim-font">
|
|
Muggenthaler-Chowdhury-Chioza syndrome
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
621063
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hyaluronidases degrade hyaluronic acid (HA), a glycosaminoglycan present in the extracellular matrix of vertebrates. Hyaluronidase-2 exhibits very low hyaluronidase activity (Lepperdinger et al., 1998; Rai et al., 2001). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By searching an EST database for sequences related to the PH-20 (600930) hyaluronidase, Lepperdinger et al. (1998) identified HYAL2 cDNAs. The HYAL2 cDNAs encode a preprotein with an N-terminal signal peptide. The predicted 452-amino acid mature protein is 36.5% identical to PH-20. Northern blot analysis indicated that HYAL2 was expressed in all human tissues tested except adult brain, and Western blot analysis detected Hyal2 protein in all mouse tissues examined except adult brain. </p><p>Strobl et al. (1998) characterized Hyal2, the mouse homolog of HYAL2. The deduced proteins are 82% identical. </p><p>By RT-PCR analysis, Chow and Knudson (2005) showed that HYAL2 was the predominant hyaluronidase expressed in human articular chondrocytes. RACE analysis identified multiple HYAL2 transcription initiation sites in human articular chondrocytes. Deletion analysis revealed the basal promoter for HYAL2 in chondrocytes, as well as a negative modulatory region. Luciferase reporter analysis showed that treatment of human articular chondrocytes or C-28/I2 immortalized human chondrocytes with catabolic cytokines did not alter HYAL2 expression, suggesting that HYAL2 is constitutively expressed and not inducibly regulated by catabolic agents in chondrocytes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lepperdinger et al. (1998) found that, unlike HYAL1 (607071), whose properties suggested that it was membrane associated, a fusion protein of HYAL2 and green fluorescent protein (GFP) localized to lysosomes of mammalian cells. HYAL2 hyaluronidase activity had a pH optimum below 4. Also in contrast to HYAL1, the HYAL2 enzyme hydrolyzed only HA of high molecular mass, yielding intermediate-sized HA fragments of approximately 20 kD, which were further hydrolyzed to small oligosaccharides by PH-20. The authors noted that the intermediate-sized HA fragments have specific biologic functions. Lepperdinger et al. (1998) concluded that HYAL2 encodes a lysosomal hyaluronidase that is present in many cell types. </p><p>Rai et al. (2001) and Dirks et al. (2002) showed that HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored protein on the cell surface and serves as a receptor for entry into the cell of the jaagsiekte sheep retrovirus (JSRV). In sheep, JSRV causes a contagious form of lung cancer that arises from epithelial cells in the lower airway, including type II alveolar and bronchiolar epithelial cells. De las Heras et al. (2000) reported that antiserum directed against the JSRV capsid protein crossreacted with 30% of human pulmonary adenocarcinoma samples but not with normal lung tissue or adenocarcinomas from other tissues. These findings supported the possibility of a viral etiology of some human lung cancers, particularly the bronchioloalveolar adenocarcinoma type, which is morphologically very similar to the sheep tumors. The viral envelope (Env) protein alone can transform cultured cells, and Danilkovitch-Miagkova et al. (2003) hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. They showed that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase, also called macrophage stimulating-1 receptor (MST1R; 600168), rendering it functionally silent. In human cells expressing a JSRV Env transgene, the Env protein physically associated with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the AKT1 (164730) and mitogen-activated protein kinase-1 (MAPK1; 176948) pathways, leading to oncogenic transformation of immortalized human bronchial epithelial cells. Danilkovitch-Miagkova et al. (2003) demonstrated activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer. </p><p>Miller (2002) provided an explanation for the discrepancy between the conclusions of Lepperdinger et al. (1998) and Rai et al. (2001), the former that HYAL2 is a lysosomal enzyme and the latter that it is a cell surface enzyme. Lepperdinger et al. (1998) linked GFP to the carboxy end of HYAL2 and found GFP in the lysosome, leading to the conclusion that HYAL2 is also in the lysosome. The findings of Rai et al. (2001) that HYAL2 is a GPI-anchored protein on the cell surface showed that GFP would likely be cleaved from HYAL2 during GPI addition, leaving HYAL2 on the cell surface and resulting in GFP transit to the lysosome for degradation. Rai et al. (2001) also showed that HYAL2 has very low hyaluronidase activity, if any, compared to serum hyaluronidase HYAL1, and that HYAL2 serves as a receptor for JSRV. </p><p>Using hyaluronan as substrate, Vigdorovich et al. (2007) demonstrated that recombinant soluble HYAL2 had hyaluronidase activity, with a sharp pH optimum of 5.6. Mutation analysis showed that hyaluronidase activity was not required for HYAL2 to function as JSRV receptor. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Strobl et al. (1998) found that the human and mouse HYAL2 genes contain 4 exons and have the same exon-intron organization. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lepperdinger et al. (1998) stated that the HYAL2 gene is identical to LUCA2, which Wei et al. (1996) positioned on a contig of human chromosome 3p21.3, a region frequently deleted in lung cancer (see 182280). Wei et al. (1996) observed that LUCA2 is located near LUCA1 (HYAL1; 607071). By analysis of an interspecific backcross, Strobl et al. (1998) mapped the Hyal2 gene to mouse chromosome 9 in a region showing homology of synteny with human 3p21. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a cohort of 33 consanguineous families with facial dysmorphism and/or skeletal dysplasia, Shaheen et al. (2016) performed autozygome analysis and whole-exome/genome sequencing and identified 2 affected members of a multiply consanguineous Saudi family with Muggenthaler-Chowdhury-Chioza syndrome (MCCS; 621063), characterized by frontonasal dysplasia and high myopia, who were homozygous for a missense mutation in the HYAL2 gene (P250L; 603551.0001). Sanger sequencing validated the mutation and its segregation with disease in the family. </p><p>By whole-exome sequencing in an extended Amish pedigree in which 5 children had frontonasal dysplasia and myopia mapping to chromosome 3p21, Muggenthaler et al. (2017) identified homozygosity for a missense mutation in the HYAL2 gene (K148R; 603551.0002) that segregated with disease and was not found in public variant databases. However, it was identified in heterozygosity in 7 of 266 Amish controls, indicating an allele frequency of 0.013 in the Amish population. </p><p>In 10 patients from 6 families with frontonasal dysplasia and myopia, with or without congenital cardiac malformations and cleft lip/palate, Fasham et al. (2022) identified homozygosity or compound heterozygosity for mutations in the HYAL2 gene (see, e.g., 603551.0002-603551.0010). The mutations segregated with disease in the respective families, and were either not found or were rare in the gnomAD database. Functional analysis in transfected cells showed reduced or absent HYAL2 protein, and cell surface expression of the mutants was absent or present at low levels compared to wildtype HYAL2. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats, with significant animal health and economic consequences. The host range of JSRV is in part limited by species-specific differences in the virus entry receptor, hyaluronidase-2 (Hyal2), which is not functional as a receptor in mice but is functional in humans. Sheep are immunotolerant of JSRV because of expression of closely related endogenous retroviruses, which are not present in humans and most other species, and that may facilitate oncogenesis. Using a replication-incompetent adeno-associated virus vector, Wootton et al. (2005) showed that expression of the JSRV envelope (Env) protein alone in lungs of mice results in tumors with a bronchioloalveolar localization like those seen in sheep. Whereas lethal disease was observed in immunodeficient mice, tumor development was almost entirely blocked in immunocompetent mice. Wootton et al. (2005) concluded that their results provided a rare example of an oncogenic viral structural protein, showed that interaction of the viral Env protein with the virus entry receptor Hyal2 is not required for tumorigenesis, and indicated that immune recognition of Env can protect against JSRV tumorigenesis. </p><p>The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum life span exceeding 30 years. In addition, it is unusually resistant to cancer. Tian et al. (2013) identified a mechanism responsible for the cancer resistance. Tian et al. (2013) found that naked mole rat fibroblasts secrete extremely high molecular mass hyaluronan (HA), which is over 5 times larger than human or mouse HA. This high molecular mass HA accumulates abundantly in naked mole rat tissues owing to the decreased activity of HA-degrading enzymes and a species-specific sequence of hyaluronan synthase-2 (HAS2; 601636). Furthermore, the naked mole rat cells are more sensitive to HA signaling, as they have a higher affinity to HA compared to mouse or human cells. Perturbation of the signaling pathways sufficient for malignant transformation of mouse fibroblasts failed to transform naked mole rat cells. However, once high molecular mass HA was removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme HYAL2, naked mole rat cells became susceptible to malignant transformation and readily formed tumors in mice. Tian et al. (2013) speculated that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels and that this trait may have then been coopted to provide cancer resistance and longevity to this species. </p><p>Chowdhury et al. (2013) found that Hyal2 -/- mice suffered from preweaning lethality, with only 9% of mice being Hyal2 -/- at weaning rather than the expected 25%. Of the viable Hyal2 -/- mice, 54% were smaller than littermates and exhibited rapid-onset lethargy, weight loss, dull coat, shortness of breath, and dilated left or right atrium, which the authors defined as the acute group. The remaining 46% developed slower onset of lethargy, loss of weight, and poor grooming, but not severe atrial dilation, which the authors defined as the nonacute group. About 43% of Hyal2 -/- mice were missing 1 kidney, but kidney loss was independent of atrial dilation and was not studied further. Both acute and nonacute groups displayed heart valve expansion, with accumulation of hyaluronan, altering the structure and organization of valves. The acute group had changes in heart structure in the upper ventricular region, close to the base of the heart. Both groups exhibited cardiac hypertrophy with an accumulation of extracellular matrix. Severe pulmonary fibrosis was observed in the acute group, but not in the nonacute group. Increased hyaluronan levels and size were seen in sera and hearts of both groups. </p><p>Muggenthaler et al. (2017) performed micro-CT studies of Hyal2 -/- mouse pups and observed an underdeveloped and underossified viscerocranium compared to littermate controls. Several central palate bones were underdeveloped, the vomer did not fuse centrally or form a head that articulated with the maxilla, and the ethmoid bone was nearly absent. Dissecting microscopy of the palates of Hyal2 -/- embryos from E18.5 to E19.5 revealed partial clefts and/or shortening of the secondary palate as well as abnormally formed rugae. Micro-CT confirmed reduced ossification and underdevelopment of the viscerocranial bones, particularly the vomer, consistent with submucosal cleft palate. The authors noted that this palatal malformation and clefting are likely to contribute significantly to the observed preweaning lethality in Hyal2-null mice. Histologic studies of P1 mice confirmed that the viscerocranial bones of all Hyal2 -/- mice were underdeveloped, and coronal sections showed the failed fusion between the epithelial surface of the vomeronasal organ and the dorsal side of the palate shelf. Hyaluronan levels were clearly increased in Hyal2-deficient tissues. The authors also noted that cor triatriatum sinister, a rare cardiac anomaly present in 1 of 7 human patients with HYAL2 mutations, had been detected in 50% of Hyal2 -/- mice. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
|
<strong>10 Selected Examples):</strong>
|
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</span>
|
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</h4>
|
|
<div>
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|
<p />
|
|
</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>.0001 MUGGENTHALER-CHOWDHURY-CHIOZA 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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|
HYAL2, PRO250LEU ({dbSNP rs781999115})
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<br />
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SNP: rs781999115,
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gnomAD: rs781999115,
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ClinVar: RCV001731160, RCV005002008
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a niece and her maternal aunt (cases 14DG1221 and 15DG1187) from a large multiply consanguineous Saudi family (family 11) with Muggenthaler-Chowdhury-Chioza syndrome (MCCS; 621063), characterized by frontonasal dysplasia and high myopia, Shaheen et al. (2016) identified homozygosity for a c.749C-T transition (c.749C-T, NM_033158.4) in the HYAL2 gene, resulting in a pro250-to-leu (P250L) substitution. Sanger sequencing confirmed the mutation and its segregation with disease in the pedigree. Both affected individuals had hypertelorism, broad nose, and micrognathia, and 1 had bilateral cleft lip and palate. </p><p>Muggenthaler et al. (2017) restudied this family (designated family 2) and noted that the P250L variant was absent in 817 ethnically matched controls and was not found in the Exome Variant Server or 1000 Genomes Project databases; however, it was present in 2 carriers in the ExAC database. Western blot analysis of transiently transfected mouse embryonic fibroblasts demonstrated a 20-fold reduction in protein level of the mutant compared to wildtype HYAL2. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, LYS148ARG
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<br />
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SNP: rs1321268291,
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ClinVar: RCV001731157, RCV005002006
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 5 affected children from a large Amish pedigree (family 1) with myopia and craniofacial dysmorphisms including hypertelorism, broad nose, and bilateral cleft lip and palate (MCCS; 621063), Muggenthaler et al. (2017) identified homozygosity for a c.443A-G transition (c.443A-G, NM_003773.4) in the HYAL2 gene, resulting in a lys148-to-arg (K148R) substitution. Sanger sequencing validated the mutation and its segregation with disease in the family. The variant was not found in the Exome Variant Server ESP, 1000 Genomes Project, or ExAC databases; however, it was identified in heterozygosity in 7 of 266 Amish controls, indicating an allele frequency of 0.013 in the Amish population. </p><p>Fasham et al. (2022) reported an Ohio Amish sister and brother (patients 1 and 2) with MCCS who were distant relatives of the Amish pedigree described by Muggenthaler et al. (2017) and were homozygous for the same K148R founder variant in the HYAL2 gene. The mutation, which segregated with disease in the family, had an allele frequency of 0.6% in the Anabaptist variant server. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, ARG277CYS
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<br />
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SNP: rs142405670,
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gnomAD: rs142405670,
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ClinVar: RCV001731161, RCV003946029, RCV005002009
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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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<div class="mim-changed mim-change"><p>In a 19-year-old Italian man (patient 3) with frontonasal dysplasia and severe myopia, who also exhibited coarctation of the aorta, ventricular septal defect, and pectus excavatum (MCCS; 621063), Fasham et al. (2022) identified compound heterozygosity for a c.829C-T transition (c.829C-T, NM_003773.4) in the HYAL2 gene, resulting in an arg277-to-cys (R277C) substitution at a highly conserved residue, and a c.883C-T transition, resulting in an arg295-to-ter (R295X) substitution. The mutations segregated with disease in the family, and both were present at low minor allele frequency in the gnomAD database (v.2.1.1; v3.1.1), only in heterozygosity. Analysis of transiently transfected mouse embryonic fibroblasts showed no detectable HYAL2 protein with the R295X mutant, whereas the R277C mutant showed very low protein levels, suggesting accelerated degradation. Immunofluorescence analysis of transfected cells showed no intracellular or cell surface expression with the R295X mutant, and no cell surface expression with the R277C mutant. </p></div>
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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 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, ARG295TER
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<br />
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SNP: rs782682203,
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gnomAD: rs782682203,
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ClinVar: RCV001731162, RCV005002010
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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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<div class="mim-changed mim-change"><p>For discussion of the c.883C-T transition (c.883C-T, NM_003773.4) in the HYAL2 gene, resulting in an arg295-to-ter (R295X) substitution, that was found in compound heterozygous state in a 19-year-old Italian man (patient 3) with frontonasal dysplasia and severe myopia (MCCS; 621063) by Fasham et al. (2022), see 603551.0003. </p></div>
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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 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, SER65TER
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<br />
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SNP: rs1553716439,
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ClinVar: RCV001731156, RCV005002005
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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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<div class="mim-changed mim-change"><p>In 2 sibs (patients 4 and 5) of North European ancestry, who died at ages 10 months and 10 days with frontonasal dysplasia, myopia, and congenital cardiac malformations (MCCS; 621063), Fasham et al. (2022) identified compound heterozygosity for a c.194C-G transversion (c.194C-G, NM_003773.4) in exon 2 of the HYAL2 gene, resulting in a ser65-to-ter (S65X) substitution, and a c.1273T-G transversion, resulting in a phe425-to-val (F425V) substitution at a highly conserved residue. The mutations segregated with disease in the family. The S65X variant was not found in the gnomAD database (v2.1.1; v3.1.1), whereas the F425V variant was present at low minor allele frequency, only in heterozygosity. Analysis of transiently transfected mouse embryonic fibroblasts showed no detectable HYAL2 protein with the S65X mutant, whereas the F425V mutant showed very low protein levels, suggesting accelerated degradation. Immunofluorescence analysis of transfected cells showed no intracellular or cell surface HYAL2 with either mutant. One sib died of complications of pulmonary hypertension, and the other sib died due to complex cardiovascular anomalies, including mitral valve atresia, hypoplastic left ventricle, double outlet right ventricle with pulmonary valve atresia, and hypoplastic pulmonary and aortoplumonary arteries with agenesis of the ductus venosus. </p></div>
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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 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, PHE425VAL
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<br />
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ClinVar: RCV005002043
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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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<div class="mim-changed mim-change"><p>For discussion of the c.1237T-G transversion (c.1237T-G, NM_003773.4) in the HYAL2 gene, resulting in a phe425-to-val (F425V) substitution, that was found in compound heterozygous state in 2 sibs (patients 4 and 5) with frontonasal dysplasia and myopia (MCCS; 621063) by Fasham et al. (2022), see 603551.0005. </p></div>
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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>.0007 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, 2-BP DEL, 1271AC
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<br />
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SNP: rs2109322411,
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ClinVar: RCV001731164, RCV005002012
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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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<div class="mim-changed mim-change"><p>In a 4-year-old German boy (patient 7) with frontonasal dysplasia, high myopia, tetralogy of Fallot, and cleft lip and palate (MCCS; 621063), Fasham et al. (2022) identified compound heterozygosity for a 2-bp deletion (c.1271_1272delAC, NM_003773.4) in the HYAL2 gene, causing a frameshift predicted to result in a premature termination codon (His424LeufsTer12) within the final exon, and a c.713T-G transversion, resulting in a leu238-to-arg (L238R) substitution at a highly conserved residue. The mutations segregated with disease in the family and were not found in the gnomAD database. Analysis of transiently transfected mouse embryonic fibroblasts showed very low protein levels with the L238R mutant, suggesting accelerated degradation, whereas the His424LeufsTer12 variant was present at levels similar to wildtype HYAL2. Immunofluorescence analysis of transfected cells showed no intracellular or cell surface expression with the truncated variant, but a low level of cell surface expression was detected for the L238R mutant compared to wildtype HYAL2. </p></div>
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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>.0008 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, LEU238ARG
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<br />
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SNP: rs2109324483,
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ClinVar: RCV001731159, RCV005002007
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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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<div class="mim-changed mim-change"><p>For discussion of the c.713T-G transversion (c.713T-G, NM_003773.4) in the HYAL2 gene, resulting in a leu238-to-arg (L238R) substitution, that was found in compound heterozygous state in a 4-year-old German boy (patient 7) with frontonasal dysplasia and high myopia (MCCS; 621063) by Fasham et al. (2022), see 603551.0007. </p></div>
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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>.0009 MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HYAL2, ARG378CYS
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<br />
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SNP: rs1553715895,
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ClinVar: RCV001731163, RCV005002011
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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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<div class="mim-changed mim-change"><p>In 3 Polish sibs (patients 8, 9, and 10) with frontonasal dysplasia, myopia, and significant cardiac malformations, including tetralogy of Fallot, hypoplastic left heart, and double-outlet right ventricle (MCCS; 621063), Fasham et al. (2022) identified compound heterozygosity for missense mutations at highly conserved residues: a c.1132C-T transition (c.1132C-T, NM_003773.4) in the HYAL2 gene, resulting in an arg378-to-cys (R378C) substitution, and a c.190G-A transition, resulting in an ala64-to-thr (A64T) substitution. The mutations, which segregated with disease in the family, were both present at low minor allele frequency in the gnomAD database (v2.1.1; v3.1.1), only in heterozygosity. Due to the impact of the COVID pandemic, no functional work could be performed on these HYAL2 variants. </p></div>
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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>.0010 MUGGENTHALER-CHOWDHURY-CHIOZA 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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HYAL2, ALA64THR
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<br />
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SNP: rs782642246,
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|
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ClinVar: RCV001731155, RCV005002004
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>For discussion of the c.190G-A transition (c.190G-A, NM_003773.4) in the HYAL2 gene, resulting in an ala64-to-thr (A64T) substitution, that was found in compound heterozygous state in 3 Polish sibs (patients 8, 9, and 10) with frontonasal dysplasia and myopia (MCCS; 621063) by Fasham et al. (2022), see 603551.0009. </p></div>
|
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
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<div>
|
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<p />
|
|
</div>
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<div>
|
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<ol>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Chow, G., Knudson, W.
|
|
<strong>Characterization of promoter elements of the human HYAL-2 gene.</strong>
|
|
J. Biol. Chem. 280: 26904-26912, 2005.
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|
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|
|
[PubMed: 15923194]
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[Full Text: https://doi.org/10.1074/jbc.M413845200]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Chowdhury, B., Hemming, R., Hombach-Klonisch, S., Flamion, B., Triggs-Raine, B.
|
|
<strong>Murine hyaluronidase 2 deficiency results in extracellular hyaluronan accumulation and severe cardiopulmonary dysfunction.</strong>
|
|
J. Biol. Chem. 288: 520-528, 2013.
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|
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|
|
[PubMed: 23172227]
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[Full Text: https://doi.org/10.1074/jbc.M112.393629]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Danilkovitch-Miagkova, A., Duh, F.-M., Kuzmin, I., Angeloni, D., Liu, S.-L., Miller, A. D., Lerman, M. I.
|
|
<strong>Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 4580-4585, 2003.
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[PubMed: 12676986]
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[Full Text: https://doi.org/10.1073/pnas.0837136100]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
De las Heras, M., Barsky, S. H., Hasleton, P., Wagner, M., Larson, E., Egan, J., Ortin, A., Gimenez-Mas, J. A., Palmarini, M., Sharp, J. M.
|
|
<strong>Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours.</strong>
|
|
Europ. Resp. J. 16: 330-332, 2000.
|
|
|
|
|
|
[PubMed: 10968511]
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[Full Text: https://doi.org/10.1034/j.1399-3003.2000.16b23.x]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dirks, C., Duh, F.-M., Rai, S. K., Lerman, M. I., Miller, A. D.
|
|
<strong>Mechanism of cell entry and transformation by enzootic nasal tumor virus.</strong>
|
|
J. Virol. 76: 2141-2149, 2002.
|
|
|
|
|
|
[PubMed: 11836391]
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|
|
[Full Text: https://doi.org/10.1128/jvi.76.5.2141-2149.2002]
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</p>
|
|
</li>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Fasham, J., Lin, S., Ghosh, P., Radio, F. C., Farrow, E. G., Thiffault, I., Kussman, J., Zhou, D., Hemming, R., Zahka, K., Chioza, B. A., Rawlins, L. E., and 28 others.
|
|
<strong>Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.</strong>
|
|
Genet. Med. 24: 631-644, 2022.
|
|
|
|
|
|
[PubMed: 34906488]
|
|
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|
|
[Full Text: https://doi.org/10.1016/j.gim.2021.10.014]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lepperdinger, G., Strobl, B., Kreil, G.
|
|
<strong>HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.</strong>
|
|
J. Biol. Chem. 273: 22466-22470, 1998.
|
|
|
|
|
|
[PubMed: 9712871]
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|
|
[Full Text: https://doi.org/10.1074/jbc.273.35.22466]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Miller, A. D.
|
|
<strong>Personal Communication.</strong>
|
|
Seattle, Wash. 12/10/2002.
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Muggenthaler, M. M. A., Chowdhury, B., Hasan, S. N., Cross, H. E., Mark, B., Harlalka, G. V., Patton, M. A., Ishida, M., Behr, E. R., Sharma, S., Zahka, K., Faqeih, E., and 12 others.
|
|
<strong>Mutations in HYAL2, encoding hyaluronidase 2, cause a syndrome of orofacial clefting and cor triatriatum sinister in humans and mice.</strong>
|
|
PLoS Genet. 13: e1006470, 2017.
|
|
|
|
|
|
[PubMed: 28081210]
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|
|
[Full Text: https://doi.org/10.1371/journal.pgen.1006470]
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D.
|
|
<strong>Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.</strong>
|
|
Proc. Nat. Acad. Sci. 98: 4443-4448, 2001.
|
|
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|
|
|
[PubMed: 11296287]
|
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|
|
[Full Text: https://doi.org/10.1073/pnas.071572898]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Shaheen, R., Patel, N., Shamseldin, H., Alzahrani, F., Al-Yamany, R., ALMoisheer, A., Ewida, N., Anazi, S., Alnemer, M., Elsheikh, M., Alfaleh, K., Alshammari, M., and 13 others.
|
|
<strong>Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.</strong>
|
|
Genet. Med. 18: 686-695, 2016.
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|
|
|
|
|
[PubMed: 26633546]
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|
|
[Full Text: https://doi.org/10.1038/gim.2015.147]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Strobl, B., Wechselberger, C., Beier, D. R., Lepperdinger, G.
|
|
<strong>Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase.</strong>
|
|
Genomics 53: 214-219, 1998.
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|
|
|
|
|
[PubMed: 9790770]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1998.5472]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V., Seluanov, A.
|
|
<strong>High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat.</strong>
|
|
Nature 499: 346-349, 2013.
|
|
|
|
|
|
[PubMed: 23783513]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature12234]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Vigdorovich, V., Miller, A. D., Strong, R. K.
|
|
<strong>Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus.</strong>
|
|
J. Virol. 81: 3124-3129, 2007.
|
|
|
|
|
|
[PubMed: 17229709]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1128/JVI.02177-06]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wei, M.-H., Latif, F., Bader, S., Kashuba, V., Chen, J.-Y., Duh, F.-M., Sekido, Y., Lee, C.-C., Geil, L., Kuzmin, I., Zabarovsky, E., Klein, G., Zbar, B., Minna, J. D., Lerman, M. I.
|
|
<strong>Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG.</strong>
|
|
Cancer Res. 56: 1487-1492, 1996.
|
|
|
|
|
|
[PubMed: 8603390]
|
|
|
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|
|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Wootton, S. K., Halbert, C. L., Miller, A. D.
|
|
<strong>Sheep retrovirus structural protein induces lung tumours.</strong>
|
|
Nature 434: 904-907, 2005.
|
|
|
|
|
|
[PubMed: 15829964]
|
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|
|
[Full Text: https://doi.org/10.1038/nature03492]
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</p>
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</li>
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</ol>
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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>
|
|
<div class="row">
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
|
<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/15/2025<br>Bao Lige - updated : 01/08/2025<br>Ada Hamosh - updated : 9/20/2013<br>Patricia A. Hartz - updated : 6/5/2007<br>Ada Hamosh - updated : 9/19/2005<br>Victor A. McKusick - updated : 6/6/2003
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