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Entry
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- *608177 - EXOSTOSIN GLYCOSYLTRANSFERASE 1; EXT1
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- OMIM
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<p>
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<span class="h4">*608177</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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<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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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608177">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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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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<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=ENSG00000182197;t=ENST00000378204" 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=2131" 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=608177" 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 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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<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=ENSG00000182197;t=ENST00000378204" 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_000127" 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_000127" 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=608177" 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="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00598&isoform_id=00598_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/EXT1" 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/1168162,1813548,12654671,20141422,46370066,119612378,189053697,298108449,530277771,543906618,559807143" 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/Q16394" 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 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=2131" 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=ENSG00000182197;t=ENST00000378204" 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=EXT1" 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=EXT1" 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+2131" 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/EXT1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:2131" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2131" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr8&hgg_gene=ENST00000378204.7&hgg_start=117794490&hgg_end=118111826&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3512" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3512" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/ext1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608177[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608177[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/EXT1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000182197" 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=EXT1" 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=EXT1" 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=EXT1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://medgen.ua.ac.be/LOVDv.2.0/home.php?select_db=EXT1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EXT1&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/PA27924" 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:3512" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0265974.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:894663" 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/EXT1#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:894663" 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/2131/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002554/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2131" 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=WBGene00004360;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-050211-3" 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:2131" 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=EXT1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1163016002, 254044004, 443520009<br />
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<strong>ICD10CM:</strong> Q78.6<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
608177
|
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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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EXOSTOSIN GLYCOSYLTRANSFERASE 1; EXT1
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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>
|
|
<span class="mim-font">
|
|
EXOSTOSIN 1<br />
|
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EXT
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EXT1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EXT1</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/8/504?start=-3&limit=10&highlight=504">8q24.11</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:117794490-118111826&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">8:117,794,490-118,111,826</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=215300,133700" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/504?start=-3&limit=10&highlight=504">
|
|
8q24.11
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Chondrosarcoma
|
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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/215300"> 215300 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
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|
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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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<tr>
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<td>
|
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<span class="mim-font">
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<p>EXT1 and EXT2 (<a href="/entry/608210">608210</a>) form a heterooligomeric complex that catalyzes the polymerization of heparan sulfate. This complex is an essential factor in a signal transduction cascade for regulation of chondrocyte differentiation, ossification, and apoptosis (summary by <a href="#9" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 screening a human chondrocyte cDNA library with cosmids that spanned breakpoints on chromosome 8q identified in patients with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>) (see <a href="#18" class="mim-tip-reference" title="Ludecke, H.-J., Wagner, M. J., Nardmann, J., La Pillo, B., Parrish, J. E., Willems, P. J., Haan, E. A., Frydman, M., Hamers, G. J. H., Wells, D. E., Horsthemke, B. <strong>Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome.</strong> Hum. Molec. Genet. 4: 31-36, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711731</a>] [<a href="https://doi.org/10.1093/hmg/4.1.31" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7711731">Ludecke et al., 1995</a>), <a href="#1" class="mim-tip-reference" title="Ahn, J., Ludecke, H.-J., Lindow, S., Horton, W. A., Lee, B., Wagner, M. J., Horsthemke, B., Wells, D. E. <strong>Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).</strong> Nature Genet. 11: 137-143, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550340</a>] [<a href="https://doi.org/10.1038/ng1095-137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550340">Ahn et al. (1995)</a> identified a cDNA encoding a putative 746-amino acid protein with a molecular mass of 86.3 kD. Northern blot analysis detected expression of a 3.4-kb transcript in all tissues tested, with highest levels in liver. The authors noted that the breakpoint region in the EXT1 gene contains 2 identical polypyrimidine tracts (CCCCCCT) that are known to be deletion hotspots, similar to the retinoblastoma gene (RB1; <a href="/entry/614041">614041</a>) (<a href="#15" class="mim-tip-reference" title="Lohmann, D. R., Brandt, B., Hopping, W., Passarge, E., Horsthemke, B. <strong>Spectrum of small length germline mutations in the RB1 gene.</strong> Hum. Molec. Genet. 3: 2187-2193, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7881418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7881418</a>] [<a href="https://doi.org/10.1093/hmg/3.12.2187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7881418">Lohmann et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7881418+7550340+7711731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Lin, X., Wells, D. <strong>Isolation of the mouse cDNA homologous to the human EXT1 gene responsible for hereditary multiple exostoses.</strong> DNA Seq. 7: 199-202, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9254013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9254013</a>] [<a href="https://doi.org/10.3109/10425179709034035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9254013">Lin and Wells (1997)</a> cloned and sequenced a mouse cDNA that is homologous to the human EXT1 gene. <a href="#16" class="mim-tip-reference" title="Lohmann, D. R., Buiting, K., Ludecke, H.-J., Horsthemke, B. <strong>The murine Ext1 gene shows a high level of sequence similarity with its human homologue and is part of a conserved linkage group on chromosome 15.</strong> Cytogenet. Cell Genet. 76: 164-166, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9186511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9186511</a>] [<a href="https://doi.org/10.1159/000134536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9186511">Lohmann et al. (1997)</a> showed that the murine Ext1 gene has a high level of sequence similarity with its human homolog. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9254013+9186511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#17" class="mim-tip-reference" title="Ludecke, H.-J., Ahn, J., Lin, X., Hill, A., Wagner, M. J., Schomburg, L., Horsthemke, B., Wells, D. E. <strong>Genomic organization and promoter structure of the human EXT1 gene.</strong> Genomics 40: 351-354, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9119404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9119404</a>] [<a href="https://doi.org/10.1006/geno.1996.4577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9119404">Ludecke et al. (1997)</a> reported that the EXT1 gene contains 11 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9119404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Ahn, J., Ludecke, H.-J., Lindow, S., Horton, W. A., Lee, B., Wagner, M. J., Horsthemke, B., Wells, D. E. <strong>Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).</strong> Nature Genet. 11: 137-143, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550340</a>] [<a href="https://doi.org/10.1038/ng1095-137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550340">Ahn et al. (1995)</a> identified the EXT1 gene within the breakpoint regions of chromosome 8q identified in patients with multiple exostoses type I. <a href="#16" class="mim-tip-reference" title="Lohmann, D. R., Buiting, K., Ludecke, H.-J., Horsthemke, B. <strong>The murine Ext1 gene shows a high level of sequence similarity with its human homologue and is part of a conserved linkage group on chromosome 15.</strong> Cytogenet. Cell Genet. 76: 164-166, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9186511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9186511</a>] [<a href="https://doi.org/10.1159/000134536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9186511">Lohmann et al. (1997)</a> found that the murine Ext1 gene is part of a conserved linkage group on mouse chromosome 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7550340+9186511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Ahn, J., Ludecke, H.-J., Lindow, S., Horton, W. A., Lee, B., Wagner, M. J., Horsthemke, B., Wells, D. E. <strong>Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).</strong> Nature Genet. 11: 137-143, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550340</a>] [<a href="https://doi.org/10.1038/ng1095-137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550340">Ahn et al. (1995)</a> suggested that EXT1 may act as a tumor suppressor gene. <a href="#7" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. <strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong> Am. J. Hum. Genet. 56: 1125-1131, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726168</a>]" pmid="7726168">Hecht et al. (1995)</a> and <a href="#23" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., Chansky, H., Matsushita, M. <strong>Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.</strong> Am. J. Hum. Genet. 56: 1132-1139, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726169</a>]" pmid="7726169">Raskind et al. (1995)</a> presented evidence suggesting that the EXT1 gene on chromosome 8 and the EXT2 gene (<a href="/entry/608210">608210</a>) on chromosome 11 have tumor suppressor function. They found loss of heterozygosity (LOH) for markers linked to these 2 genes in chondrosarcomas originating in individuals with multiple exostoses (see <a href="/entry/133700">133700</a>) as well as in sporadic chondrosarcomas. The proteins encoded by the EXT1 and EXT2 genes play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. To explain the fact that normal bone growth occurs concurrently with abnormal exostosis tumor growth, <a href="#7" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. <strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong> Am. J. Hum. Genet. 56: 1125-1131, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726168</a>]" pmid="7726168">Hecht et al. (1995)</a> and <a href="#23" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., Chansky, H., Matsushita, M. <strong>Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.</strong> Am. J. Hum. Genet. 56: 1132-1139, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726169</a>]" pmid="7726169">Raskind et al. (1995)</a> proposed a 2-hit tumor formation model according to the Knudson hypothesis (<a href="#12" class="mim-tip-reference" title="Knudson, A. G., Jr. <strong>Mutation and cancer: statistical study of retinoblastoma.</strong> Proc. Nat. Acad. Sci. 68: 820-823, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5279523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5279523</a>] [<a href="https://doi.org/10.1073/pnas.68.4.820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5279523">Knudson, 1971</a>). In this model, a single germline mutation results in the predisposition for disease and a second somatic mutational hit, usually LOH, allows for aberrant growth. <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> noted that although the EXT1 protein is ubiquitously expressed in many tissues, the only known effect of mutated or inactivated EXT1 appears to be specific to actively growing bone, allowing inappropriate bone growth to be juxtaposed to the growth plate; as the bone continues to grow, the exostoses appear to migrate toward the diaphysis. At puberty, with growth plate fusion, linear growth ceases and no new exostoses develop. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7550340+7726169+8981950+5279523+7726168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="McCormick, C., Leduc, Y., Martindale, D., Mattison, K., Esford, L. E., Dyer, A. P., Tufaro, F. <strong>The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.</strong> Nature Genet. 19: 158-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620772</a>] [<a href="https://doi.org/10.1038/514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620772">McCormick et al. (1998)</a> showed that EXT1 is an endoplasmic reticulum (ER)-resident type II transmembrane glycoprotein whose expression in cells results in the alteration of the synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs). Two EXT1 variants containing missense mutations related to multiple exostoses failed to alter cell surface glycosaminoglycans, despite retaining their ER localization. By testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, <a href="#20" class="mim-tip-reference" title="McCormick, C., Duncan, G., Goutsos, K. T., Tufaro, F. <strong>The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate.</strong> Proc. Nat. Acad. Sci. 97: 668-673, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10639137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10639137</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10639137[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.2.668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10639137">McCormick et al. (2000)</a> showed that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1. Instead, it appears that EXT1 and EXT2 form a heterooligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone, suggesting that the complex represents the biologically relevant form of the enzyme(s). These findings provided a rationale for the causation of hereditary multiple exostoses by loss of activity in either of the 2 EXT genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9620772+10639137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bovee, J. V. M. G., Cleton-Jansen, A.-M., Wuyts, W., Caethoven, G., Taminiau, A. H. M., Bakker, E., Van Hul, W., Cornelisse, C. J., Hogendoorn, P. C. W. <strong>EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.</strong> Am. J. Hum. Genet. 65: 689-698, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441575</a>] [<a href="https://doi.org/10.1086/302532" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441575">Bovee et al. (1999)</a> conducted studies to determine whether inactivation of both alleles of an EXT gene, according to the tumor suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a single dominant-negative way. They studied LOH and DNA ploidy in 8 sporadic and 6 hereditary osteochondromas. EXT1 and EXT2 mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. They demonstrated that osteochondroma is a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. The 2 patients with multiple osteochondromas demonstrated a germline mutation combined with the loss of the remaining wildtype allele in 3 osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene was required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations in the EXT2 gene were found in any of these cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Ropero, S., Setien, F., Espada, J., Fraga, M. F., Herranz, M., Asp, J., Benassi, M. S., Franchi, A., Patino, A., Ward, L. S., Bovee, J., Cigudosa, J. C., Wim, W., Esteller, M. <strong>Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells.</strong> Hum. Molec. Genet. 13: 2753-2765, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385438</a>] [<a href="https://doi.org/10.1093/hmg/ddh298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385438">Ropero et al. (2004)</a> reported that EXT1 function was abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Epigenetic inactivation of EXT1 led to loss of heparan sulfate (HS) synthesis that was reversed by a DNA demethylating agent. Reintroduction of EXT1 into EXT1 methylation-deficient cancer cells induced tumor suppressor-like features, including reduced colony formation density and tumor growth in nude mouse xenograft models. By screening 79 human cancer cell lines and 454 primary tumors from different cell types, the authors found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and nonmelanoma skin cancer. <a href="#25" class="mim-tip-reference" title="Ropero, S., Setien, F., Espada, J., Fraga, M. F., Herranz, M., Asp, J., Benassi, M. S., Franchi, A., Patino, A., Ward, L. S., Bovee, J., Cigudosa, J. C., Wim, W., Esteller, M. <strong>Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells.</strong> Hum. Molec. Genet. 13: 2753-2765, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385438</a>] [<a href="https://doi.org/10.1093/hmg/ddh298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385438">Ropero et al. (2004)</a> concluded that EXT1 epigenetic inactivation, leading to abrogation of HS biosynthesis, is an important step in the processes of tumor onset and progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Multiple Exostoses Type I</em></strong></p><p>
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In 2 of 23 unrelated families with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#1" class="mim-tip-reference" title="Ahn, J., Ludecke, H.-J., Lindow, S., Horton, W. A., Lee, B., Wagner, M. J., Horsthemke, B., Wells, D. E. <strong>Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).</strong> Nature Genet. 11: 137-143, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550340</a>] [<a href="https://doi.org/10.1038/ng1095-137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550340">Ahn et al. (1995)</a> identified a 1-bp deletion in the EXT1 gene (<a href="#0001">608177.0001</a>) that segregated with the disease. In 4 of 6 EXT families demonstrating linkage to the EXT1 locus on chromosome 8, <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified 3 germline mutations in the EXT1 gene that segregated with the disease phenotype in each family (<a href="#0002">608177.0002</a>-<a href="#0004">608177.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8981950+7550340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 7 of 17 families (41%) with EXT, <a href="#22" class="mim-tip-reference" title="Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. <strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 61: 520-528, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326317</a>] [<a href="https://doi.org/10.1086/515505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326317">Philippe et al. (1997)</a> identified mutations in the EXT1 gene, including 5 novel mutations (see, e.g., <a href="#0007">608177.0007</a> and <a href="#0009">608177.0009</a>). Five of the families (29%) had mutations in the EXT2 gene. <a href="#27" class="mim-tip-reference" title="Wells, D. E., Hill, A., Lin, X., Ahn, J., Brown, N., Wagner, M. J. <strong>Identification of novel mutations in the human EXT1 tumor suppressor gene.</strong> Hum. Genet. 99: 612-615, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150727</a>] [<a href="https://doi.org/10.1007/s004390050415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150727">Wells et al. (1997)</a> identified 6 mutations in the EXT1 gene in 6 unrelated EXT families showing linkage to chromosome 8. One of the mutations was the same 1-bp deletion in exon 6 that was previously reported in 2 independent EXT families (<a href="#0001">608177.0001</a>). The other 5 mutations were novel. In each case, the mutation was predicted to result in a truncated or nonfunctional EXT1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9150727+9326317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J. <strong>Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 62: 346-354, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463333</a>] [<a href="https://doi.org/10.1086/301726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463333">Wuyts et al. (1998)</a> analyzed the EXT1 and EXT2 genes in 26 EXT families originating from 9 countries. Of the 26 families, 10 had an EXT1 mutation and 10 had an EXT2 mutation. Twelve of these mutations had not previously been described. From a review of these and previously reported mutations, <a href="#28" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J. <strong>Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 62: 346-354, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463333</a>] [<a href="https://doi.org/10.1086/301726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463333">Wuyts et al. (1998)</a> concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these 2 genes cause premature termination of the EXT proteins, whereas missense mutations are rare. The authors concluded that the development of exostoses is mainly due to loss of function of EXT genes, consistent with the hypothesis that the EXT genes have a tumor suppressor function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9463333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 11 isolated cases of exostoses and 20 families with EXT, <a href="#24" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., III, Matsushita, M., Wijsman, E. M., Wells, D. E., Chapman, N., Sandell, L. J., Wagner, M., Houck, J. <strong>Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.</strong> Hum. Mutat. 11: 231-239, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521425</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521425">Raskind et al. (1998)</a> identified 12 novel EXT1 mutations, including 5 frameshift deletions or insertions, 1 codon deletion, and 6 single basepair substitutions, distributed across 8 of the exons. Only 2 of the mutations were identified in more than 1 family. Three mutations affected sites in which alterations were previously reported. Nonchain-terminating missense mutations were identified in codons 280 and 340, both coding for conserved arginine residues. <a href="#24" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., III, Matsushita, M., Wijsman, E. M., Wells, D. E., Chapman, N., Sandell, L. J., Wagner, M., Houck, J. <strong>Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.</strong> Hum. Mutat. 11: 231-239, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521425</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521425">Raskind et al. (1998)</a> suggested that these residues may be crucial to the function of this protein. One of the mutations (<a href="#0008">608177.0008</a>) was identified in a Chamorro native on Guam, where EXT is unusually frequent. They concluded that 45% of the isolated cases and 77% of the familial cases could be attributed to abnormalities in EXT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 23 of 43 Japanese families with hereditary multiple exostoses, <a href="#26" class="mim-tip-reference" title="Seki, H., Kubota, T., Ikegawa, S., Haga, N., Fujioka, F., Ohzeki, S., Wakui, K., Yoshikawa, H., Takaoka, K., Fukushima, Y. <strong>Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses.</strong> Am. J. Med. Genet. 99: 59-62, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170095</a>] [<a href="https://doi.org/10.1002/1096-8628(20010215)99:1<59::aid-ajmg1115>3.0.co;2-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170095">Seki et al. (2001)</a> found 21 mutations, of which 18 were novel. Seventeen (40%) of the 23 families had a mutation in the EXT1 gene and 6 (14%) had a mutation in the EXT2 gene. Of the 17 families with EXT1 mutations, 13 had those causing premature termination of the EXT1 protein, and 4 showed missense mutations. All 4 EXT1 missense mutations occurred in the arginine residue at codon 340 (R340L; <a href="#0004">608177.0004</a>). R340 is known as a critical site for expression of heparan sulfate glycosaminoglycans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein. In contrast to the findings of <a href="#26" class="mim-tip-reference" title="Seki, H., Kubota, T., Ikegawa, S., Haga, N., Fujioka, F., Ohzeki, S., Wakui, K., Yoshikawa, H., Takaoka, K., Fukushima, Y. <strong>Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses.</strong> Am. J. Med. Genet. 99: 59-62, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170095</a>] [<a href="https://doi.org/10.1002/1096-8628(20010215)99:1<59::aid-ajmg1115>3.0.co;2-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170095">Seki et al. (2001)</a>, <a href="#30" class="mim-tip-reference" title="Xu, L., Xia, J., Jiang, H., Zhou, J., Li, H., Wang, D., Pan, Q., Long, Z., Fan, C., Deng, H.-X. <strong>Mutation analysis of hereditary multiple exostoses in the Chinese.</strong> Hum. Genet. 105: 45-50, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480354</a>] [<a href="https://doi.org/10.1007/s004399900058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480354">Xu et al. (1999)</a> detected more mutations in EXT2 than in EXT1 in Chinese patients (33% and 14%, respectively). An excess of EXT1 mutations was found in Caucasian patients, however, by <a href="#22" class="mim-tip-reference" title="Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. <strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 61: 520-528, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326317</a>] [<a href="https://doi.org/10.1086/515505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326317">Philippe et al. (1997)</a> and <a href="#28" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J. <strong>Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 62: 346-354, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463333</a>] [<a href="https://doi.org/10.1086/301726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463333">Wuyts et al. (1998)</a>. In both Caucasian patients, as studied by <a href="#24" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., III, Matsushita, M., Wijsman, E. M., Wells, D. E., Chapman, N., Sandell, L. J., Wagner, M., Houck, J. <strong>Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.</strong> Hum. Mutat. 11: 231-239, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521425</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521425">Raskind et al. (1998)</a>, and Japanese patients, more EXT1 mutations were identified in familial cases than in sporadic cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326317+10480354+9463333+11170095+9521425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 82 Japanese patients with hereditary multiple exostoses by <a href="#26" class="mim-tip-reference" title="Seki, H., Kubota, T., Ikegawa, S., Haga, N., Fujioka, F., Ohzeki, S., Wakui, K., Yoshikawa, H., Takaoka, K., Fukushima, Y. <strong>Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses.</strong> Am. J. Med. Genet. 99: 59-62, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170095</a>] [<a href="https://doi.org/10.1002/1096-8628(20010215)99:1<59::aid-ajmg1115>3.0.co;2-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170095">Seki et al. (2001)</a>, 4 patients developed malignancy and their mutations (3 in EXT1 and 1 in EXT2) were all different, suggesting that malignant transformation is not directly related to a particular mutation in EXT1 or EXT2, but more likely involves other genetic factors. Loss of heterozygosity has been detected in chondrosarcoma not only at the EXT loci but also at others such as 10q (RET; <a href="/entry/164761">164761</a>) and 3q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Wuyts, W., Van Hul, W. <strong>Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes.</strong> Hum. Mutat. 15: 220-227, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10679937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10679937</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10679937">Wuyts and Van Hul (2000)</a> stated that 49 different EXT1 and 25 different EXT2 mutations had been identified in patients with multiple exostoses and that mutations in these 2 genes were responsible for over 70% of the EXT cases. Most of the mutations cause loss of function, which is consistent with the presumed tumor suppressor function of the EXT genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10679937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="McCormick, C., Leduc, Y., Martindale, D., Mattison, K., Esford, L. E., Dyer, A. P., Tufaro, F. <strong>The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.</strong> Nature Genet. 19: 158-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620772</a>] [<a href="https://doi.org/10.1038/514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620772">McCormick et al. (1998)</a> showed that the missense mutations G339D (<a href="#0007">608177.0007</a>) and R340C (<a href="#0009">608177.0009</a>) abrogate the ability of exostosin-1 to synthesize heparan sulfate (HS). <a href="#3" class="mim-tip-reference" title="Cheung, P. K., McCormick, C., Crawford, B. E., Esko, J. D., Tufaro, F., Duncan, G. <strong>Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity.</strong> Am. J. Hum. Genet. 69: 55-66, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391482</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11391482[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/321278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391482">Cheung et al. (2001)</a> used a functional assay that detects HS expression on the cell surface of an EXT1-deficient cell line to test other missense mutant exostosin proteins for their ability to rescue HS biosynthesis in vivo. Their results showed that EXT1 mutants bearing 6 of these missense mutations are also defective in HS expression, but surprisingly, 4 missense mutations that had been considered etiologic were phenotypically indistinguishable from wildtype EXT1. Three of these 4 'active' mutations affect amino acids that are not conserved among vertebrates and invertebrates, whereas all of the HS-biosynthesis null mutations affect only conserved amino acids. Further, substitution or deletion of each of these 4 residues does not abrogate HS biosynthesis. Taken together, these results indicated that several of the reported etiologic mutant EXT forms retain the ability to synthesize and express HS on the cell surface. <a href="#3" class="mim-tip-reference" title="Cheung, P. K., McCormick, C., Crawford, B. E., Esko, J. D., Tufaro, F., Duncan, G. <strong>Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity.</strong> Am. J. Hum. Genet. 69: 55-66, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391482</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11391482[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/321278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11391482">Cheung et al. (2001)</a> suggested that these mutations may represent rare genetic polymorphisms in the EXT1 gene or may interfere with functions of EXT1 that are involved in the pathogenesis of hereditary multiple exostoses. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9620772+11391482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hall, C. R., Cole, W. G., Haynes, R., Hecht, J. T. <strong>Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis.</strong> Am. J. Med. Genet. 112: 1-5, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12239711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12239711</a>] [<a href="https://doi.org/10.1002/ajmg.10635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12239711">Hall et al. (2002)</a> reported the direct sequencing and LOH analysis of 12 exostoses in 10 hereditary multiple exostoses families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, there was only 1 isolated case in which 2 somatic mutations, a deletion and an LOH, were present. <a href="#6" class="mim-tip-reference" title="Hall, C. R., Cole, W. G., Haynes, R., Hecht, J. T. <strong>Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis.</strong> Am. J. Med. Genet. 112: 1-5, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12239711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12239711</a>] [<a href="https://doi.org/10.1002/ajmg.10635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12239711">Hall et al. (2002)</a> developed alternative models of pathogenesis, including a second mutational event in genes other than EXT1 and EXT2, such as the EXTL1 (<a href="/entry/601738">601738</a>), EXTL2 (<a href="/entry/602411">602411</a>), and EXTL3 (<a href="/entry/605744">605744</a>) genes. <a href="#30" class="mim-tip-reference" title="Xu, L., Xia, J., Jiang, H., Zhou, J., Li, H., Wang, D., Pan, Q., Long, Z., Fan, C., Deng, H.-X. <strong>Mutation analysis of hereditary multiple exostoses in the Chinese.</strong> Hum. Genet. 105: 45-50, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480354</a>] [<a href="https://doi.org/10.1007/s004399900058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480354">Xu et al. (1999)</a> found no germline mutations in the EXTL1 and EXTL2 genes of patients with hereditary multiple exostoses. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12239711+10480354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 11 of 23 German patients with multiple exostoses, <a href="#9" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al. (2009)</a> identified 11 different novel mutations in the EXT1 gene (see, e.g., <a href="#0012">608177.0012</a>). Eleven patients had mutations in the EXT2 gene, and 1 patient had no detectable mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 79 unrelated Italian patients with multiple exostoses type I, <a href="#5" class="mim-tip-reference" title="Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. <strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong> Hum. Molec. Genet. 28: 2133-2142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>] [<a href="https://doi.org/10.1093/hmg/ddz046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30806661">Fusco et al. (2019)</a> identified 62 different heterozygous mutations in the EXT1 gene, of which 36 were novel. The mutations were identified by direct sequencing or by MLPA analysis followed by confirmation with quantitative real-time PCR. The mutations included 23 frameshifts, 22 nonsense, 6 missense, 9 splicing, and 2 intragenic rearrangements. The most common mutation was R340H (<a href="#0013">608177.0013</a>), which occurred in 5 families. To evaluate the functional importance of EXT1 domains, <a href="#5" class="mim-tip-reference" title="Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. <strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong> Hum. Molec. Genet. 28: 2133-2142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>] [<a href="https://doi.org/10.1093/hmg/ddz046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30806661">Fusco et al. (2019)</a> tested the effects of 2 mutations with a premature termination (C355X and Leu427ArgfsTer14), comprising the N-terminal exostosin domain or the C-terminal glycosyltransferase family 64 domain, in U2OS cells. The mutated proteins had abnormal localization patterns. These mutant EXT1 proteins were also expressed in HEK293 cells, which showed slower growth compared to cells expressing wildtype EXT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30806661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Chondrosarcoma</em></strong></p><p>
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In a patient (individual 6) with chondrosarcoma (<a href="/entry/215300">215300</a>), <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified an EXT1 mutation in the constitutional DNA (<a href="#0005">608177.0005</a>), but the tumor tissue had retained the wildtype allele. In a patient (individual 10) with sporadic chondrosarcoma, <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified a mutation in the tumor tissue (<a href="#0006">608177.0006</a>), which was not present in the constitutional DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Trichorhinophalangeal Syndrome Type II</em></strong></p><p>
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Exostoses in the contiguous gene syndrome trichorhinophalangeal syndrome type II (<a href="/entry/150230">150230</a>) are caused by loss of functional copies of the EXT1 gene (<a href="#18" class="mim-tip-reference" title="Ludecke, H.-J., Wagner, M. J., Nardmann, J., La Pillo, B., Parrish, J. E., Willems, P. J., Haan, E. A., Frydman, M., Hamers, G. J. H., Wells, D. E., Horsthemke, B. <strong>Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome.</strong> Hum. Molec. Genet. 4: 31-36, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711731</a>] [<a href="https://doi.org/10.1093/hmg/4.1.31" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7711731">Ludecke et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7711731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To define the developmental role of heparan sulfate in mammalian species, <a href="#11" class="mim-tip-reference" title="Inatani, M., Irie, F., Plump, A. S., Tessier-Lavigne, M., Yamaguchi, Y. <strong>Mammalian brain morphogenesis and midline axon guidance require heparan sulfate.</strong> Science 302: 1044-1046, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14605369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14605369</a>] [<a href="https://doi.org/10.1126/science.1090497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14605369">Inatani et al. (2003)</a> conditionally disrupted the heparan sulfate polymerizing enzyme Ext1 in the embryonic mouse brain. The Ext1-null brain exhibited patterning defects that were composites of those caused by mutations of multiple heparan sulfate-binding morphogens. Furthermore, the Ext1-null brain displayed severe guidance errors in major commissural tracts, revealing a pivotal role of heparan sulfate in midline axon guidance. <a href="#11" class="mim-tip-reference" title="Inatani, M., Irie, F., Plump, A. S., Tessier-Lavigne, M., Yamaguchi, Y. <strong>Mammalian brain morphogenesis and midline axon guidance require heparan sulfate.</strong> Science 302: 1044-1046, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14605369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14605369</a>] [<a href="https://doi.org/10.1126/science.1090497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14605369">Inatani et al. (2003)</a> concluded that heparan sulfate is essential for mammalian brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14605369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 introducing a hypomorphic mutation in the Ext1 gene, <a href="#13" class="mim-tip-reference" title="Koziel, L., Kunath, M., Kelly, O. G., Vortkamp, A. <strong>Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification.</strong> Dev. Cell 6: 801-813, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15177029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15177029</a>] [<a href="https://doi.org/10.1016/j.devcel.2004.05.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15177029">Koziel et al. (2004)</a> developed mice producing significantly reduced levels of heparan sulfate. Homozygous mutant embryos survived until embryonic day 14.5 at a nonmendelian ratio of 14%. Only 4% were recovered at embryonic day 16.5. Mutant embryos were small and edematous. They had heart defects, reduced skeleton size with fused vertebrae, shortened fore- and hindlimbs, fused elbow and knee joints, and occasionally syndactylies of digits. Homozygous mutant mice showed an extended distribution of Ihh (<a href="/entry/600726">600726</a>) signaling during embryonic chondrocyte differentiation, and ectopic heparan sulfate restricted Ihh signaling. The authors concluded that heparan sulfate binds hedgehog in the extracellular space and negatively regulates the range of hedgehog signaling in a dose-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15177029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Matsumoto, K., Irie, F., Mackem, S., Yamaguchi, Y. <strong>A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses.</strong> Proc. Nat. Acad. Sci. 107: 10932-10937, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20534475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20534475</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20534475[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.0914642107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20534475">Matsumoto et al. (2010)</a> created a line of mice with random deletion of Ext1 in a small fraction of chondrocytes. Mutant mice developed osteochondromas of the wrist, fibula, shoulder, and rib. A high proportion of mutant animals also showed bowing deformity of the radius, subluxation/dislocation of the radial head, scoliosis, and mild abnormalities in the growth plate and joint cartilage. Genotyping showed that osteochondromas contained a high proportion of wildtype chondrocytes, in addition to Est1-null chondrocytes. The pattern of gene expression in osteochondromas more resembled that of ectopic growth plates than of neoplasms. <a href="#19" class="mim-tip-reference" title="Matsumoto, K., Irie, F., Mackem, S., Yamaguchi, Y. <strong>A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses.</strong> Proc. Nat. Acad. Sci. 107: 10932-10937, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20534475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20534475</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20534475[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.0914642107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20534475">Matsumoto et al. (2010)</a> hypothesized that Est1-null chondrocytes are required for initiation of osteochondromas, but the subsequent growth of osteochondromas is not directly due to upregulated proliferation of mutant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20534475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>13 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608177[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886039356 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039356;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=rs886039356" 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=rs886039356" 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=RCV000255784 OR RCV000702125 OR RCV001003498 OR RCV004567807" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000255784, RCV000702125, RCV001003498, RCV004567807" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000255784...</a>
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<p>In 2 of 23 unrelated families with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#1" class="mim-tip-reference" title="Ahn, J., Ludecke, H.-J., Lindow, S., Horton, W. A., Lee, B., Wagner, M. J., Horsthemke, B., Wells, D. E. <strong>Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).</strong> Nature Genet. 11: 137-143, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550340</a>] [<a href="https://doi.org/10.1038/ng1095-137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550340">Ahn et al. (1995)</a> identified a 1-bp deletion (2120T) in the EXT1 gene, resulting in a premature stop codon. The mutation cosegregated with the disease in the families over 2 and 3 generations, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2130042099 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2130042099;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=rs2130042099" 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=rs2130042099" 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=RCV001942031 OR RCV002267784 OR RCV003229075 OR RCV003395320" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001942031, RCV002267784, RCV003229075, RCV003395320" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001942031...</a>
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<p>In 2 unrelated families with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified a 1-bp deletion (1364delC) in exon 1 of the EXT1 gene, resulting in a premature stop codon at nucleotide 1403. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 EXOSTOSES, MULTIPLE, TYPE I</strong>
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EXT1, 4-BP INS, NT1035
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2130043564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2130043564;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=rs2130043564" 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=rs2130043564" 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=RCV000002600" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002600" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002600</a>
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<p>In a family with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified a 4-bp insertion (1035ins4) in exon 1 of the EXT1 gene, resulting in a premature stop codon at nucleotide 1213. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 EXOSTOSES, MULTIPLE, TYPE I</strong>
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EXT1, ARG340LEU
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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> rs119103287 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103287;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/rs119103287?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=rs119103287" 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=rs119103287" 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=RCV000002601 OR RCV001003502 OR RCV005031383" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002601, RCV001003502, RCV005031383" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002601...</a>
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<p>In a family with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified a 1635G-T transversion in exon 2 of the EXT1 gene, resulting in an arg339-to-leu (R339L) substitution. It was subsequently discovered that the mutation was a 1670G-T transversion that resulted in an arg340-to-leu (R340L) substitution (<a href="#10" class="mim-tip-reference" title="Hogue, D. <strong>Personal Communication.</strong> Houston, Tex 2/6/1998."None>Hogue, 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CHONDROSARCOMA</strong>
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EXT1, 1-BP INS, 2077C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554578798 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554578798;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=rs1554578798" 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=rs1554578798" 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=RCV000554263 OR RCV000627404 OR RCV002267737" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000554263, RCV000627404, RCV002267737" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000554263...</a>
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<p>In a patient with chondrosarcoma (<a href="/entry/215300">215300</a>), <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified a 1-bp insertion (2077-2082insC) in the EXT1 gene in the patient's constitutional DNA, resulting in a frameshift and a premature stop codon at nucleotide 2208 in exon 6. Interestingly, the tumor tissue retained the wildtype allele, but had LOH for chromosome 3q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CHONDROSARCOMA, SOMATIC</strong>
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EXT1, 8-BP DEL, NT1178
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776540 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776540;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=rs587776540" 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=rs587776540" 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=RCV000002603" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002603" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002603</a>
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<p>In the tumor tissue of a patient (individual 10) with sporadic chondrosarcoma (<a href="/entry/215300">215300</a>), <a href="#8" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D. <strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong> Am. J. Hum. Genet. 60: 80-86, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981950</a>]" pmid="8981950">Hecht et al. (1997)</a> identified an 8-bp deletion (1178del8) in the EXT1 gene, resulting in a premature stop codon at nucleotide 1213. This mutation did not appear in the patient's constitutional DNA, suggesting somatic origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0007 EXOSTOSES, MULTIPLE, TYPE I</strong>
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</h4>
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EXT1, GLY339ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs119103288 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103288;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=rs119103288" 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=rs119103288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002604 OR RCV001003501 OR RCV003311634" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002604, RCV001003501, RCV003311634" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002604...</a>
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<p>In a family with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#22" class="mim-tip-reference" title="Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. <strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 61: 520-528, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326317</a>] [<a href="https://doi.org/10.1086/515505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326317">Philippe et al. (1997)</a> identified a gly339-to-asp (G339D) missense mutation in exon 2 of the EXT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="McCormick, C., Leduc, Y., Martindale, D., Mattison, K., Esford, L. E., Dyer, A. P., Tufaro, F. <strong>The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.</strong> Nature Genet. 19: 158-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620772</a>] [<a href="https://doi.org/10.1038/514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620772">McCormick et al. (1998)</a> showed that the G339D missense mutation abrogates heparan sulfate biosynthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 EXOSTOSES, MULTIPLE, TYPE I</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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<div style="float: left;">
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EXT1, TYR119TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs119103289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103289;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=rs119103289" 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=rs119103289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002605 OR RCV002468956" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002605, RCV002468956" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002605...</a>
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</span>
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<span class="mim-text-font">
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<p>In a Chamorro native on Guam, <a href="#24" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., III, Matsushita, M., Wijsman, E. M., Wells, D. E., Chapman, N., Sandell, L. J., Wagner, M., Houck, J. <strong>Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.</strong> Hum. Mutat. 11: 231-239, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521425</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521425">Raskind et al. (1998)</a> demonstrated that multiple exostoses were associated with a 108C-A transversion in exon 1 of the EXT1 gene, leading to a stop codon, tyr119-to-ter (Y119X). <a href="#24" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., III, Matsushita, M., Wijsman, E. M., Wells, D. E., Chapman, N., Sandell, L. J., Wagner, M., Houck, J. <strong>Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.</strong> Hum. Mutat. 11: 231-239, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521425</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521425">Raskind et al. (1998)</a> suggested that identification of the Chamorro mutation could allow investigation of a possible founder effect in this population, which has an unusually high frequency of EXT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 EXOSTOSES, MULTIPLE, TYPE I</strong>
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</span>
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</h4>
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EXT1, ARG340CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs119103290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103290;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=rs119103290" 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=rs119103290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002606 OR RCV000255752 OR RCV001003500 OR RCV002512681 OR RCV004739279 OR RCV005031384" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002606, RCV000255752, RCV001003500, RCV002512681, RCV004739279, RCV005031384" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002606...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a family with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#22" class="mim-tip-reference" title="Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. <strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 61: 520-528, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326317</a>] [<a href="https://doi.org/10.1086/515505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326317">Philippe et al. (1997)</a> identified an arg340-to-cys (R340C) mutation in exon 2 of the EXT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="McCormick, C., Leduc, Y., Martindale, D., Mattison, K., Esford, L. E., Dyer, A. P., Tufaro, F. <strong>The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.</strong> Nature Genet. 19: 158-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620772</a>] [<a href="https://doi.org/10.1038/514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620772">McCormick et al. (1998)</a> showed that the R340C missense mutation abrogates heparan sulfate biosynthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 EXOSTOSES, MULTIPLE, TYPE I</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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EXT1, IVS1DS, G-C
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</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">rs886039353 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039353;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=rs886039353" 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=rs886039353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002607 OR RCV001239443" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002607, RCV001239443" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002607...</a>
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<p>In affected members of a large consanguineous Pakistani family with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#4" class="mim-tip-reference" title="Faiyaz-Ul-Haque, M., Ahmad, W., Zaidi, S. H. E., Hussain, S., Haque, S., Ahmad, M., Cohn, D. H., Tsui, L.-C. <strong>Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis).</strong> Clin. Genet. 66: 144-151, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15253765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15253765</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00275.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15253765">Faiyaz-Ul-Haque et al. (2004)</a> identified a G-to-C transversion at the conserved splice donor site in intron 1 of the EXT1 gene, predicted to result in a null allele. All affected individuals, and no unaffected individuals, had bilateral overriding of the fourth toe. This feature was present at birth, allowing earlier diagnosis of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15253765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1586993159 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1586993159;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=rs1586993159" 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=rs1586993159" 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=RCV000002608" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002608" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002608</a>
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<p>In affected members of a large consanguineous Pakistani family with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#4" class="mim-tip-reference" title="Faiyaz-Ul-Haque, M., Ahmad, W., Zaidi, S. H. E., Hussain, S., Haque, S., Ahmad, M., Cohn, D. H., Tsui, L.-C. <strong>Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis).</strong> Clin. Genet. 66: 144-151, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15253765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15253765</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00275.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15253765">Faiyaz-Ul-Haque et al. (2004)</a> identified a 1-bp insertion (1664insA) in exon 8 of the EXT1 gene, predicted to produce a frameshift at codon 555 resulting in a premature termination 10 codons downstream. Bilateral overriding of the second or third toes was observed in all affected individuals except for 1 asymptomatic female and 1 mildly affected female. No unaffected individuals had this feature, which was present at birth and allowed earlier diagnosis of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15253765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 EXOSTOSES, MULTIPLE, TYPE I</strong>
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EXT1, IVS1DS, 4-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1586279285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1586279285;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=rs1586279285" 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=rs1586279285" 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=RCV000002609 OR RCV003478970 OR RCV005089148" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002609, RCV003478970, RCV005089148" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002609...</a>
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<p>In a German patient with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#9" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al. (2009)</a> identified a heterozygous 4-bp deletion (962+1-962+4del4) in the 5-prime splice donor site of intron 1 of the EXT1 gene. The mutation results in the skipping of exon 2 and a frameshift with premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 EXOSTOSES, MULTIPLE, TYPE I</strong>
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EXT1, ARG340HIS
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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> rs119103287 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119103287;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/rs119103287?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=rs119103287" 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=rs119103287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000254839 OR RCV000630812 OR RCV001263553 OR RCV004739643" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000254839, RCV000630812, RCV001263553, RCV004739643" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000254839...</a>
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<p>In 5 unrelated Italian patients with multiple exostoses type I (EXT1; <a href="/entry/133700">133700</a>), <a href="#5" class="mim-tip-reference" title="Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. <strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong> Hum. Molec. Genet. 28: 2133-2142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>] [<a href="https://doi.org/10.1093/hmg/ddz046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30806661">Fusco et al. (2019)</a> identified a heterozygous c.1019G-A transition (c.1019G-A, NM_000127.2) in exon 2 of the EXT1 gene, resulting in an arg340-to-his (R340H) substitution. The mutation was identified by direct sequencing of the EXT1 gene. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30806661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<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="Ahn1995" class="mim-anchor"></a>
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Ahn, J., Ludecke, H.-J., Lindow, S., Horton, W. A., Lee, B., Wagner, M. J., Horsthemke, B., Wells, D. E.
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<strong>Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).</strong>
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Nature Genet. 11: 137-143, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550340" 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/ng1095-137" target="_blank">Full Text</a>]
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Bovee, J. V. M. G., Cleton-Jansen, A.-M., Wuyts, W., Caethoven, G., Taminiau, A. H. M., Bakker, E., Van Hul, W., Cornelisse, C. J., Hogendoorn, P. C. W.
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<strong>EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.</strong>
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Am. J. Hum. Genet. 65: 689-698, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302532" target="_blank">Full Text</a>]
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Cheung, P. K., McCormick, C., Crawford, B. E., Esko, J. D., Tufaro, F., Duncan, G.
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<strong>Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity.</strong>
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Am. J. Hum. Genet. 69: 55-66, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11391482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11391482</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11391482[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=11391482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/321278" target="_blank">Full Text</a>]
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Faiyaz-Ul-Haque, M., Ahmad, W., Zaidi, S. H. E., Hussain, S., Haque, S., Ahmad, M., Cohn, D. H., Tsui, L.-C.
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<strong>Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis).</strong>
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Clin. Genet. 66: 144-151, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15253765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15253765</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15253765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2004.00275.x" target="_blank">Full Text</a>]
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Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others.
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<strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong>
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Hum. Molec. Genet. 28: 2133-2142, 2019.
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<a id="Raskind1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Raskind, W. H., Conrad, E. U., Chansky, H., Matsushita, M.
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<strong>Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.</strong>
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Am. J. Hum. Genet. 56: 1132-1139, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726169</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7726169" 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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<a id="24" class="mim-anchor"></a>
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<a id="Raskind1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Raskind, W. H., Conrad, E. U., III, Matsushita, M., Wijsman, E. M., Wells, D. E., Chapman, N., Sandell, L. J., Wagner, M., Houck, J.
|
|
<strong>Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.</strong>
|
|
Hum. Mutat. 11: 231-239, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521425</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<231::AID-HUMU8>3.0.CO;2-K" target="_blank">Full Text</a>]
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Ropero2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ropero, S., Setien, F., Espada, J., Fraga, M. F., Herranz, M., Asp, J., Benassi, M. S., Franchi, A., Patino, A., Ward, L. S., Bovee, J., Cigudosa, J. C., Wim, W., Esteller, M.
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<strong>Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells.</strong>
|
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Hum. Molec. Genet. 13: 2753-2765, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385438</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh298" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Seki2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Seki, H., Kubota, T., Ikegawa, S., Haga, N., Fujioka, F., Ohzeki, S., Wakui, K., Yoshikawa, H., Takaoka, K., Fukushima, Y.
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<strong>Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses.</strong>
|
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Am. J. Med. Genet. 99: 59-62, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170095</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/1096-8628(20010215)99:1<59::aid-ajmg1115>3.0.co;2-z" target="_blank">Full Text</a>]
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<a id="27" class="mim-anchor"></a>
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<a id="Wells1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wells, D. E., Hill, A., Lin, X., Ahn, J., Brown, N., Wagner, M. J.
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<strong>Identification of novel mutations in the human EXT1 tumor suppressor gene.</strong>
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Hum. Genet. 99: 612-615, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150727</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050415" target="_blank">Full Text</a>]
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Wuyts1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J.
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<strong>Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.</strong>
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Am. J. Hum. Genet. 62: 346-354, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463333</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9463333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/301726" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="Wuyts2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wuyts, W., Van Hul, W.
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<strong>Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes.</strong>
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Hum. Mutat. 15: 220-227, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10679937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10679937</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10679937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K" target="_blank">Full Text</a>]
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Xu1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, L., Xia, J., Jiang, H., Zhou, J., Li, H., Wang, D., Pan, Q., Long, Z., Fan, C., Deng, H.-X.
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<strong>Mutation analysis of hereditary multiple exostoses in the Chinese.</strong>
|
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Hum. Genet. 105: 45-50, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480354</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10480354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004399900058" target="_blank">Full Text</a>]
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Hilary J. Vernon - updated : 11/06/2020
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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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Patricia A. Hartz - updated : 11/13/2012<br>Cassandra L. Kniffin - updated : 11/10/2009<br>George E. Tiller - updated : 5/22/2007<br>Marla J. F. O'Neill - updated : 4/20/2005<br>Patricia A. Hartz - updated : 8/9/2004<br>Ada Hamosh - updated : 12/3/2003
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</span>
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</div>
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</div>
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<div>
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<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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Cassandra L. Kniffin : 10/17/2003
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</span>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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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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carol : 11/06/2020
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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 : 07/24/2020<br>carol : 04/29/2019<br>carol : 10/11/2013<br>carol : 9/19/2013<br>mgross : 11/13/2012<br>terry : 11/13/2012<br>alopez : 6/17/2011<br>alopez : 1/10/2011<br>wwang : 12/8/2009<br>ckniffin : 11/10/2009<br>wwang : 5/30/2007<br>terry : 5/22/2007<br>carol : 2/8/2007<br>carol : 8/1/2006<br>mgross : 3/16/2006<br>wwang : 4/28/2005<br>wwang : 4/25/2005<br>terry : 4/20/2005<br>mgross : 8/10/2004<br>terry : 8/9/2004<br>alopez : 12/9/2003<br>terry : 12/3/2003<br>tkritzer : 11/21/2003<br>carol : 10/30/2003<br>ckniffin : 10/29/2003
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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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</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> 608177
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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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EXOSTOSIN GLYCOSYLTRANSFERASE 1; EXT1
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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">
|
|
EXOSTOSIN 1<br />
|
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EXT
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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: EXT1</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>SNOMEDCT:</strong> 1163016002, 254044004, 443520009;
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<strong>ICD10CM:</strong> Q78.6;
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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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<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: 8q24.11
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 8:117,794,490-118,111,826 </span>
|
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</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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<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>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
8q24.11
|
|
</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Chondrosarcoma
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
215300
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Exostoses, multiple, type 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
133700
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>EXT1 and EXT2 (608210) form a heterooligomeric complex that catalyzes the polymerization of heparan sulfate. This complex is an essential factor in a signal transduction cascade for regulation of chondrocyte differentiation, ossification, and apoptosis (summary by Heinritz et al., 2009). </p>
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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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<span class="mim-text-font">
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<p>By screening a human chondrocyte cDNA library with cosmids that spanned breakpoints on chromosome 8q identified in patients with multiple exostoses type I (EXT1; 133700) (see Ludecke et al., 1995), Ahn et al. (1995) identified a cDNA encoding a putative 746-amino acid protein with a molecular mass of 86.3 kD. Northern blot analysis detected expression of a 3.4-kb transcript in all tissues tested, with highest levels in liver. The authors noted that the breakpoint region in the EXT1 gene contains 2 identical polypyrimidine tracts (CCCCCCT) that are known to be deletion hotspots, similar to the retinoblastoma gene (RB1; 614041) (Lohmann et al., 1994). </p><p>Lin and Wells (1997) cloned and sequenced a mouse cDNA that is homologous to the human EXT1 gene. Lohmann et al. (1997) showed that the murine Ext1 gene has a high level of sequence similarity with its human homolog. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</h4>
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<span class="mim-text-font">
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<p>Ludecke et al. (1997) reported that the EXT1 gene contains 11 exons. </p>
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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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<span class="mim-text-font">
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<p>Ahn et al. (1995) identified the EXT1 gene within the breakpoint regions of chromosome 8q identified in patients with multiple exostoses type I. Lohmann et al. (1997) found that the murine Ext1 gene is part of a conserved linkage group on mouse chromosome 15. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Ahn et al. (1995) suggested that EXT1 may act as a tumor suppressor gene. Hecht et al. (1995) and Raskind et al. (1995) presented evidence suggesting that the EXT1 gene on chromosome 8 and the EXT2 gene (608210) on chromosome 11 have tumor suppressor function. They found loss of heterozygosity (LOH) for markers linked to these 2 genes in chondrosarcomas originating in individuals with multiple exostoses (see 133700) as well as in sporadic chondrosarcomas. The proteins encoded by the EXT1 and EXT2 genes play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. To explain the fact that normal bone growth occurs concurrently with abnormal exostosis tumor growth, Hecht et al. (1995) and Raskind et al. (1995) proposed a 2-hit tumor formation model according to the Knudson hypothesis (Knudson, 1971). In this model, a single germline mutation results in the predisposition for disease and a second somatic mutational hit, usually LOH, allows for aberrant growth. Hecht et al. (1997) noted that although the EXT1 protein is ubiquitously expressed in many tissues, the only known effect of mutated or inactivated EXT1 appears to be specific to actively growing bone, allowing inappropriate bone growth to be juxtaposed to the growth plate; as the bone continues to grow, the exostoses appear to migrate toward the diaphysis. At puberty, with growth plate fusion, linear growth ceases and no new exostoses develop. </p><p>McCormick et al. (1998) showed that EXT1 is an endoplasmic reticulum (ER)-resident type II transmembrane glycoprotein whose expression in cells results in the alteration of the synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs). Two EXT1 variants containing missense mutations related to multiple exostoses failed to alter cell surface glycosaminoglycans, despite retaining their ER localization. By testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, McCormick et al. (2000) showed that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1. Instead, it appears that EXT1 and EXT2 form a heterooligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone, suggesting that the complex represents the biologically relevant form of the enzyme(s). These findings provided a rationale for the causation of hereditary multiple exostoses by loss of activity in either of the 2 EXT genes. </p><p>Bovee et al. (1999) conducted studies to determine whether inactivation of both alleles of an EXT gene, according to the tumor suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a single dominant-negative way. They studied LOH and DNA ploidy in 8 sporadic and 6 hereditary osteochondromas. EXT1 and EXT2 mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. They demonstrated that osteochondroma is a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. The 2 patients with multiple osteochondromas demonstrated a germline mutation combined with the loss of the remaining wildtype allele in 3 osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene was required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations in the EXT2 gene were found in any of these cases. </p><p>Ropero et al. (2004) reported that EXT1 function was abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Epigenetic inactivation of EXT1 led to loss of heparan sulfate (HS) synthesis that was reversed by a DNA demethylating agent. Reintroduction of EXT1 into EXT1 methylation-deficient cancer cells induced tumor suppressor-like features, including reduced colony formation density and tumor growth in nude mouse xenograft models. By screening 79 human cancer cell lines and 454 primary tumors from different cell types, the authors found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and nonmelanoma skin cancer. Ropero et al. (2004) concluded that EXT1 epigenetic inactivation, leading to abrogation of HS biosynthesis, is an important step in the processes of tumor onset and progression. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Multiple Exostoses Type I</em></strong></p><p>
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In 2 of 23 unrelated families with multiple exostoses type I (EXT1; 133700), Ahn et al. (1995) identified a 1-bp deletion in the EXT1 gene (608177.0001) that segregated with the disease. In 4 of 6 EXT families demonstrating linkage to the EXT1 locus on chromosome 8, Hecht et al. (1997) identified 3 germline mutations in the EXT1 gene that segregated with the disease phenotype in each family (608177.0002-608177.0004). </p><p>In 7 of 17 families (41%) with EXT, Philippe et al. (1997) identified mutations in the EXT1 gene, including 5 novel mutations (see, e.g., 608177.0007 and 608177.0009). Five of the families (29%) had mutations in the EXT2 gene. Wells et al. (1997) identified 6 mutations in the EXT1 gene in 6 unrelated EXT families showing linkage to chromosome 8. One of the mutations was the same 1-bp deletion in exon 6 that was previously reported in 2 independent EXT families (608177.0001). The other 5 mutations were novel. In each case, the mutation was predicted to result in a truncated or nonfunctional EXT1 protein. </p><p>Wuyts et al. (1998) analyzed the EXT1 and EXT2 genes in 26 EXT families originating from 9 countries. Of the 26 families, 10 had an EXT1 mutation and 10 had an EXT2 mutation. Twelve of these mutations had not previously been described. From a review of these and previously reported mutations, Wuyts et al. (1998) concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these 2 genes cause premature termination of the EXT proteins, whereas missense mutations are rare. The authors concluded that the development of exostoses is mainly due to loss of function of EXT genes, consistent with the hypothesis that the EXT genes have a tumor suppressor function. </p><p>Among 11 isolated cases of exostoses and 20 families with EXT, Raskind et al. (1998) identified 12 novel EXT1 mutations, including 5 frameshift deletions or insertions, 1 codon deletion, and 6 single basepair substitutions, distributed across 8 of the exons. Only 2 of the mutations were identified in more than 1 family. Three mutations affected sites in which alterations were previously reported. Nonchain-terminating missense mutations were identified in codons 280 and 340, both coding for conserved arginine residues. Raskind et al. (1998) suggested that these residues may be crucial to the function of this protein. One of the mutations (608177.0008) was identified in a Chamorro native on Guam, where EXT is unusually frequent. They concluded that 45% of the isolated cases and 77% of the familial cases could be attributed to abnormalities in EXT1. </p><p>In 23 of 43 Japanese families with hereditary multiple exostoses, Seki et al. (2001) found 21 mutations, of which 18 were novel. Seventeen (40%) of the 23 families had a mutation in the EXT1 gene and 6 (14%) had a mutation in the EXT2 gene. Of the 17 families with EXT1 mutations, 13 had those causing premature termination of the EXT1 protein, and 4 showed missense mutations. All 4 EXT1 missense mutations occurred in the arginine residue at codon 340 (R340L; 608177.0004). R340 is known as a critical site for expression of heparan sulfate glycosaminoglycans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein. In contrast to the findings of Seki et al. (2001), Xu et al. (1999) detected more mutations in EXT2 than in EXT1 in Chinese patients (33% and 14%, respectively). An excess of EXT1 mutations was found in Caucasian patients, however, by Philippe et al. (1997) and Wuyts et al. (1998). In both Caucasian patients, as studied by Raskind et al. (1998), and Japanese patients, more EXT1 mutations were identified in familial cases than in sporadic cases. </p><p>In a study of 82 Japanese patients with hereditary multiple exostoses by Seki et al. (2001), 4 patients developed malignancy and their mutations (3 in EXT1 and 1 in EXT2) were all different, suggesting that malignant transformation is not directly related to a particular mutation in EXT1 or EXT2, but more likely involves other genetic factors. Loss of heterozygosity has been detected in chondrosarcoma not only at the EXT loci but also at others such as 10q (RET; 164761) and 3q. </p><p>Wuyts and Van Hul (2000) stated that 49 different EXT1 and 25 different EXT2 mutations had been identified in patients with multiple exostoses and that mutations in these 2 genes were responsible for over 70% of the EXT cases. Most of the mutations cause loss of function, which is consistent with the presumed tumor suppressor function of the EXT genes. </p><p>McCormick et al. (1998) showed that the missense mutations G339D (608177.0007) and R340C (608177.0009) abrogate the ability of exostosin-1 to synthesize heparan sulfate (HS). Cheung et al. (2001) used a functional assay that detects HS expression on the cell surface of an EXT1-deficient cell line to test other missense mutant exostosin proteins for their ability to rescue HS biosynthesis in vivo. Their results showed that EXT1 mutants bearing 6 of these missense mutations are also defective in HS expression, but surprisingly, 4 missense mutations that had been considered etiologic were phenotypically indistinguishable from wildtype EXT1. Three of these 4 'active' mutations affect amino acids that are not conserved among vertebrates and invertebrates, whereas all of the HS-biosynthesis null mutations affect only conserved amino acids. Further, substitution or deletion of each of these 4 residues does not abrogate HS biosynthesis. Taken together, these results indicated that several of the reported etiologic mutant EXT forms retain the ability to synthesize and express HS on the cell surface. Cheung et al. (2001) suggested that these mutations may represent rare genetic polymorphisms in the EXT1 gene or may interfere with functions of EXT1 that are involved in the pathogenesis of hereditary multiple exostoses. </p><p>Hall et al. (2002) reported the direct sequencing and LOH analysis of 12 exostoses in 10 hereditary multiple exostoses families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, there was only 1 isolated case in which 2 somatic mutations, a deletion and an LOH, were present. Hall et al. (2002) developed alternative models of pathogenesis, including a second mutational event in genes other than EXT1 and EXT2, such as the EXTL1 (601738), EXTL2 (602411), and EXTL3 (605744) genes. Xu et al. (1999) found no germline mutations in the EXTL1 and EXTL2 genes of patients with hereditary multiple exostoses. </p><p>In 11 of 23 German patients with multiple exostoses, Heinritz et al. (2009) identified 11 different novel mutations in the EXT1 gene (see, e.g., 608177.0012). Eleven patients had mutations in the EXT2 gene, and 1 patient had no detectable mutations. </p><p>In 79 unrelated Italian patients with multiple exostoses type I, Fusco et al. (2019) identified 62 different heterozygous mutations in the EXT1 gene, of which 36 were novel. The mutations were identified by direct sequencing or by MLPA analysis followed by confirmation with quantitative real-time PCR. The mutations included 23 frameshifts, 22 nonsense, 6 missense, 9 splicing, and 2 intragenic rearrangements. The most common mutation was R340H (608177.0013), which occurred in 5 families. To evaluate the functional importance of EXT1 domains, Fusco et al. (2019) tested the effects of 2 mutations with a premature termination (C355X and Leu427ArgfsTer14), comprising the N-terminal exostosin domain or the C-terminal glycosyltransferase family 64 domain, in U2OS cells. The mutated proteins had abnormal localization patterns. These mutant EXT1 proteins were also expressed in HEK293 cells, which showed slower growth compared to cells expressing wildtype EXT1. </p><p><strong><em>Chondrosarcoma</em></strong></p><p>
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In a patient (individual 6) with chondrosarcoma (215300), Hecht et al. (1997) identified an EXT1 mutation in the constitutional DNA (608177.0005), but the tumor tissue had retained the wildtype allele. In a patient (individual 10) with sporadic chondrosarcoma, Hecht et al. (1997) identified a mutation in the tumor tissue (608177.0006), which was not present in the constitutional DNA. </p><p><strong><em>Trichorhinophalangeal Syndrome Type II</em></strong></p><p>
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Exostoses in the contiguous gene syndrome trichorhinophalangeal syndrome type II (150230) are caused by loss of functional copies of the EXT1 gene (Ludecke et al., 1995). </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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To define the developmental role of heparan sulfate in mammalian species, Inatani et al. (2003) conditionally disrupted the heparan sulfate polymerizing enzyme Ext1 in the embryonic mouse brain. The Ext1-null brain exhibited patterning defects that were composites of those caused by mutations of multiple heparan sulfate-binding morphogens. Furthermore, the Ext1-null brain displayed severe guidance errors in major commissural tracts, revealing a pivotal role of heparan sulfate in midline axon guidance. Inatani et al. (2003) concluded that heparan sulfate is essential for mammalian brain development. </p><p>By introducing a hypomorphic mutation in the Ext1 gene, Koziel et al. (2004) developed mice producing significantly reduced levels of heparan sulfate. Homozygous mutant embryos survived until embryonic day 14.5 at a nonmendelian ratio of 14%. Only 4% were recovered at embryonic day 16.5. Mutant embryos were small and edematous. They had heart defects, reduced skeleton size with fused vertebrae, shortened fore- and hindlimbs, fused elbow and knee joints, and occasionally syndactylies of digits. Homozygous mutant mice showed an extended distribution of Ihh (600726) signaling during embryonic chondrocyte differentiation, and ectopic heparan sulfate restricted Ihh signaling. The authors concluded that heparan sulfate binds hedgehog in the extracellular space and negatively regulates the range of hedgehog signaling in a dose-dependent manner. </p><p>Matsumoto et al. (2010) created a line of mice with random deletion of Ext1 in a small fraction of chondrocytes. Mutant mice developed osteochondromas of the wrist, fibula, shoulder, and rib. A high proportion of mutant animals also showed bowing deformity of the radius, subluxation/dislocation of the radial head, scoliosis, and mild abnormalities in the growth plate and joint cartilage. Genotyping showed that osteochondromas contained a high proportion of wildtype chondrocytes, in addition to Est1-null chondrocytes. The pattern of gene expression in osteochondromas more resembled that of ectopic growth plates than of neoplasms. Matsumoto et al. (2010) hypothesized that Est1-null chondrocytes are required for initiation of osteochondromas, but the subsequent growth of osteochondromas is not directly due to upregulated proliferation of mutant cells. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 EXOSTOSES, MULTIPLE, TYPE I</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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EXT1, 1-BP DEL, 2120T
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<br />
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SNP: rs886039356,
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ClinVar: RCV000255784, RCV000702125, RCV001003498, RCV004567807
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 of 23 unrelated families with multiple exostoses type I (EXT1; 133700), Ahn et al. (1995) identified a 1-bp deletion (2120T) in the EXT1 gene, resulting in a premature stop codon. The mutation cosegregated with the disease in the families over 2 and 3 generations, respectively. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 EXOSTOSES, MULTIPLE, TYPE I</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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EXT1, 1-BP DEL, 1364C
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<br />
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SNP: rs2130042099,
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ClinVar: RCV001942031, RCV002267784, RCV003229075, RCV003395320
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated families with multiple exostoses type I (EXT1; 133700), Hecht et al. (1997) identified a 1-bp deletion (1364delC) in exon 1 of the EXT1 gene, resulting in a premature stop codon at nucleotide 1403. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 EXOSTOSES, MULTIPLE, TYPE I</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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EXT1, 4-BP INS, NT1035
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<br />
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SNP: rs2130043564,
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ClinVar: RCV000002600
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with multiple exostoses type I (EXT1; 133700), Hecht et al. (1997) identified a 4-bp insertion (1035ins4) in exon 1 of the EXT1 gene, resulting in a premature stop codon at nucleotide 1213. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 EXOSTOSES, MULTIPLE, TYPE I</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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EXT1, ARG340LEU
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<br />
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SNP: rs119103287,
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gnomAD: rs119103287,
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ClinVar: RCV000002601, RCV001003502, RCV005031383
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with multiple exostoses type I (EXT1; 133700), Hecht et al. (1997) identified a 1635G-T transversion in exon 2 of the EXT1 gene, resulting in an arg339-to-leu (R339L) substitution. It was subsequently discovered that the mutation was a 1670G-T transversion that resulted in an arg340-to-leu (R340L) substitution (Hogue, 1998). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CHONDROSARCOMA</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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EXT1, 1-BP INS, 2077C
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<br />
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SNP: rs1554578798,
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ClinVar: RCV000554263, RCV000627404, RCV002267737
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with chondrosarcoma (215300), Hecht et al. (1997) identified a 1-bp insertion (2077-2082insC) in the EXT1 gene in the patient's constitutional DNA, resulting in a frameshift and a premature stop codon at nucleotide 2208 in exon 6. Interestingly, the tumor tissue retained the wildtype allele, but had LOH for chromosome 3q. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 CHONDROSARCOMA, SOMATIC</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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EXT1, 8-BP DEL, NT1178
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<br />
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SNP: rs587776540,
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ClinVar: RCV000002603
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In the tumor tissue of a patient (individual 10) with sporadic chondrosarcoma (215300), Hecht et al. (1997) identified an 8-bp deletion (1178del8) in the EXT1 gene, resulting in a premature stop codon at nucleotide 1213. This mutation did not appear in the patient's constitutional DNA, suggesting somatic origin. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 EXOSTOSES, MULTIPLE, TYPE I</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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EXT1, GLY339ASP
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<br />
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SNP: rs119103288,
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ClinVar: RCV000002604, RCV001003501, RCV003311634
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with multiple exostoses type I (EXT1; 133700), Philippe et al. (1997) identified a gly339-to-asp (G339D) missense mutation in exon 2 of the EXT1 gene. </p><p>McCormick et al. (1998) showed that the G339D missense mutation abrogates heparan sulfate biosynthesis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 EXOSTOSES, MULTIPLE, TYPE I</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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EXT1, TYR119TER
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<br />
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SNP: rs119103289,
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ClinVar: RCV000002605, RCV002468956
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Chamorro native on Guam, Raskind et al. (1998) demonstrated that multiple exostoses were associated with a 108C-A transversion in exon 1 of the EXT1 gene, leading to a stop codon, tyr119-to-ter (Y119X). Raskind et al. (1998) suggested that identification of the Chamorro mutation could allow investigation of a possible founder effect in this population, which has an unusually high frequency of EXT. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 EXOSTOSES, MULTIPLE, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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EXT1, ARG340CYS
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<br />
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SNP: rs119103290,
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ClinVar: RCV000002606, RCV000255752, RCV001003500, RCV002512681, RCV004739279, RCV005031384
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a family with multiple exostoses type I (EXT1; 133700), Philippe et al. (1997) identified an arg340-to-cys (R340C) mutation in exon 2 of the EXT1 gene. </p><p>McCormick et al. (1998) showed that the R340C missense mutation abrogates heparan sulfate biosynthesis. </p>
|
|
</span>
|
|
</div>
|
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<div>
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 EXOSTOSES, MULTIPLE, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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EXT1, IVS1DS, G-C
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<br />
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|
|
SNP: rs886039353,
|
|
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|
|
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|
|
ClinVar: RCV000002607, RCV001239443
|
|
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|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large consanguineous Pakistani family with multiple exostoses type I (EXT1; 133700), Faiyaz-Ul-Haque et al. (2004) identified a G-to-C transversion at the conserved splice donor site in intron 1 of the EXT1 gene, predicted to result in a null allele. All affected individuals, and no unaffected individuals, had bilateral overriding of the fourth toe. This feature was present at birth, allowing earlier diagnosis of the disorder. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 EXOSTOSES, MULTIPLE, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EXT1, 1-BP INS, 1664A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1586993159,
|
|
|
|
|
|
|
|
ClinVar: RCV000002608
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large consanguineous Pakistani family with multiple exostoses type I (EXT1; 133700), Faiyaz-Ul-Haque et al. (2004) identified a 1-bp insertion (1664insA) in exon 8 of the EXT1 gene, predicted to produce a frameshift at codon 555 resulting in a premature termination 10 codons downstream. Bilateral overriding of the second or third toes was observed in all affected individuals except for 1 asymptomatic female and 1 mildly affected female. No unaffected individuals had this feature, which was present at birth and allowed earlier diagnosis of the disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 EXOSTOSES, MULTIPLE, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EXT1, IVS1DS, 4-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1586279285,
|
|
|
|
|
|
|
|
ClinVar: RCV000002609, RCV003478970, RCV005089148
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a German patient with multiple exostoses type I (EXT1; 133700), Heinritz et al. (2009) identified a heterozygous 4-bp deletion (962+1-962+4del4) in the 5-prime splice donor site of intron 1 of the EXT1 gene. The mutation results in the skipping of exon 2 and a frameshift with premature termination. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 EXOSTOSES, MULTIPLE, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EXT1, ARG340HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119103287,
|
|
|
|
|
|
gnomAD: rs119103287,
|
|
|
|
|
|
ClinVar: RCV000254839, RCV000630812, RCV001263553, RCV004739643
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 unrelated Italian patients with multiple exostoses type I (EXT1; 133700), Fusco et al. (2019) identified a heterozygous c.1019G-A transition (c.1019G-A, NM_000127.2) in exon 2 of the EXT1 gene, resulting in an arg340-to-his (R340H) substitution. The mutation was identified by direct sequencing of the EXT1 gene. Functional studies were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ahn, J., Ludecke, H.-J., Lindow, S., Horton, W. A., Lee, B., Wagner, M. J., Horsthemke, B., Wells, D. E.
|
|
<strong>Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).</strong>
|
|
Nature Genet. 11: 137-143, 1995.
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|
|
[PubMed: 7550340]
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[Full Text: https://doi.org/10.1038/ng1095-137]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bovee, J. V. M. G., Cleton-Jansen, A.-M., Wuyts, W., Caethoven, G., Taminiau, A. H. M., Bakker, E., Van Hul, W., Cornelisse, C. J., Hogendoorn, P. C. W.
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<strong>EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.</strong>
|
|
Am. J. Hum. Genet. 65: 689-698, 1999.
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[PubMed: 10441575]
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[Full Text: https://doi.org/10.1086/302532]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cheung, P. K., McCormick, C., Crawford, B. E., Esko, J. D., Tufaro, F., Duncan, G.
|
|
<strong>Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity.</strong>
|
|
Am. J. Hum. Genet. 69: 55-66, 2001.
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[PubMed: 11391482]
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[Full Text: https://doi.org/10.1086/321278]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Faiyaz-Ul-Haque, M., Ahmad, W., Zaidi, S. H. E., Hussain, S., Haque, S., Ahmad, M., Cohn, D. H., Tsui, L.-C.
|
|
<strong>Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis).</strong>
|
|
Clin. Genet. 66: 144-151, 2004.
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[PubMed: 15253765]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2004.00275.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">
|
|
Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others.
|
|
<strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong>
|
|
Hum. Molec. Genet. 28: 2133-2142, 2019.
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[PubMed: 30806661]
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[Full Text: https://doi.org/10.1093/hmg/ddz046]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hall, C. R., Cole, W. G., Haynes, R., Hecht, J. T.
|
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<strong>Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis.</strong>
|
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Am. J. Med. Genet. 112: 1-5, 2002.
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[PubMed: 12239711]
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[Full Text: https://doi.org/10.1002/ajmg.10635]
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|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M.
|
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<strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong>
|
|
Am. J. Hum. Genet. 56: 1125-1131, 1995.
|
|
|
|
|
|
[PubMed: 7726168]
|
|
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hecht, J. T., Hogue, D., Wang, Y., Blanton, S. H., Wagner, M., Strong, L. C., Raskind, W., Hansen, M. F., Wells, D.
|
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<strong>Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.</strong>
|
|
Am. J. Hum. Genet. 60: 80-86, 1997.
|
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|
|
[PubMed: 8981950]
|
|
|
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|
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</p>
|
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</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G.
|
|
<strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong>
|
|
Ann. Hum. Genet. 73: 283-291, 2009.
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[PubMed: 19344451]
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|
|
[Full Text: https://doi.org/10.1111/j.1469-1809.2009.00508.x]
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|
|
</p>
|
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</li>
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hogue, D.
|
|
<strong>Personal Communication.</strong>
|
|
Houston, Tex 2/6/1998.
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Inatani, M., Irie, F., Plump, A. S., Tessier-Lavigne, M., Yamaguchi, Y.
|
|
<strong>Mammalian brain morphogenesis and midline axon guidance require heparan sulfate.</strong>
|
|
Science 302: 1044-1046, 2003.
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|
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|
|
[PubMed: 14605369]
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|
|
[Full Text: https://doi.org/10.1126/science.1090497]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Knudson, A. G., Jr.
|
|
<strong>Mutation and cancer: statistical study of retinoblastoma.</strong>
|
|
Proc. Nat. Acad. Sci. 68: 820-823, 1971.
|
|
|
|
|
|
[PubMed: 5279523]
|
|
|
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|
|
[Full Text: https://doi.org/10.1073/pnas.68.4.820]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Koziel, L., Kunath, M., Kelly, O. G., Vortkamp, A.
|
|
<strong>Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification.</strong>
|
|
Dev. Cell 6: 801-813, 2004.
|
|
|
|
|
|
[PubMed: 15177029]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.devcel.2004.05.009]
|
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|
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|
|
</p>
|
|
</li>
|
|
|
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<li>
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