2996 lines
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Entry
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- *604846 - HEPARAN SULFATE 6-O-SULFOTRANSFERASE 1; HS6ST1
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- OMIM
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<p>
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<span class="h4">*604846</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604846">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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000136720;t=ENST00000259241" 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=9394" 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=604846" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000136720;t=ENST00000259241" 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_004807" 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_004807" 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=604846" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=07274&isoform_id=07274_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/HS6ST1" 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/3073775,12654713,62822187,119615763,119615764,119615765,148747866,194374515,194381474,194385596,211829178,211829192,211829340,211829420,229463049" 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/O60243" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=9394" 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=ENSG00000136720;t=ENST00000259241" 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=HS6ST1" 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=HS6ST1" 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+9394" 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/HS6ST1" 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:9394" 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/9394" 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=chr2&hgg_gene=ENST00000259241.7&hgg_start=128265480&hgg_end=128318868&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604846[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=604846[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000136720" 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=HS6ST1" 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=HS6ST1" 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=HS6ST1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HS6ST1&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/PA35102" 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:5201" 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/FBgn0038755.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:1354958" 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/HS6ST1#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:1354958" 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/9394/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=9394" 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=WBGene00002031;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-050524-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9394" 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=HS6ST1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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604846
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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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HEPARAN SULFATE 6-O-SULFOTRANSFERASE 1; HS6ST1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
HS6ST
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HS6ST1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HS6ST1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/2/631?start=-3&limit=10&highlight=631">2q14.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:128265480-128318868&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'})">2:128,265,480-128,318,868</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/2/631?start=-3&limit=10&highlight=631">
|
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2q14.3
|
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</a>
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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{Hypogonadotropic hypogonadism 15 with or without anosmia}
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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/614880"> 614880 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604846" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604846" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
|
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<span class="mim-text-font">
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<p>Heparan sulfate (HS) 6-O-sulfotransferase catalyzes the transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate to position 6 of the N-sulfoglucosamine residue of heparan sulfate (<a href="#1" class="mim-tip-reference" title="Habuchi, H., Kobayashi, M., Kimata, K. <strong>Molecular characterization and expression of heparan-sulfate 6-sulfotransferase: complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells.</strong> J. Biol. Chem. 273: 9208-9213, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535912</a>] [<a href="https://doi.org/10.1074/jbc.273.15.9208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9535912">Habuchi et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9535912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 fetal brain cDNA library with a Chinese hamster Hs6st cDNA, <a href="#1" class="mim-tip-reference" title="Habuchi, H., Kobayashi, M., Kimata, K. <strong>Molecular characterization and expression of heparan-sulfate 6-sulfotransferase: complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells.</strong> J. Biol. Chem. 273: 9208-9213, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535912</a>] [<a href="https://doi.org/10.1074/jbc.273.15.9208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9535912">Habuchi et al. (1998)</a> isolated human HS6ST cDNAs. The predicted 401-amino acid human HS6ST protein is a type II transmembrane protein, with an N-terminal transmembrane domain. A putative cleavage site occurs near the C-terminal end of the transmembrane domain. HS6ST contains 2 potential N-glycosylation sites. It does not share significant sequence similarity to other known sulfotransferases, including HS2ST. HS6ST does not contain a conserved 3-prime-phosphoadenosine 5-prime-phosphosulfate-binding site sequence, or a 'P-loop,' which is found in most sulfotransferases and has been implicated as an ATP- or GTP-binding site. Northern blot analysis of human fetal brain RNA detected a 3.9-kb HS6ST transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9535912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Habuchi, H., Tanaka, M., Habuchi, O., Yoshida, K., Suzuki, H., Ban, K., Kimata, K. <strong>The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine.</strong> J. Biol. Chem. 275: 2859-2868, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644753</a>] [<a href="https://doi.org/10.1074/jbc.275.4.2859" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644753">Habuchi et al. (2000)</a> cloned Hs6st1 from a mouse brain cDNA library. The deduced 401-amino acid protein has characteristics of a type II transmembrane protein, with a short N-terminal segment followed by a hydrophobic sequence. It also contains 2 N-glycosylation sites. Northern blot analysis detected a 3.9-kb Hs6st1 transcript in most mouse tissues examined, with predominant expression in liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Habuchi, H., Kobayashi, M., Kimata, K. <strong>Molecular characterization and expression of heparan-sulfate 6-sulfotransferase: complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells.</strong> J. Biol. Chem. 273: 9208-9213, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535912</a>] [<a href="https://doi.org/10.1074/jbc.273.15.9208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9535912">Habuchi et al. (1998)</a> found that recombinant HS6ST expressed in mammalian cells exhibited HS6ST activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9535912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Habuchi, H., Tanaka, M., Habuchi, O., Yoshida, K., Suzuki, H., Ban, K., Kimata, K. <strong>The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine.</strong> J. Biol. Chem. 275: 2859-2868, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644753</a>] [<a href="https://doi.org/10.1074/jbc.275.4.2859" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644753">Habuchi et al. (2000)</a> demonstrated elevated 6-O-sulfotransferase activity in the cytoplasm of COS-7 cells transfected with mouse Hs6st1. Hs6st1 was also secreted into the medium. Hs6st1 showed 6-O-sulfotransferase activity against HS, N-sulfated heparosan, heparin, and some HS derivatives. It did not show sulfotransferase activity toward other glycosaminoglycans examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 experiments in C. elegans, <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> observed that HS cell-specifically regulates neural branching in vivo in concert with other genes that are associated with hypogonadotropic hypogonadism (see <a href="/entry/147950">147950</a>), including KAL1 (<a href="/entry/300836">300836</a>), FGF8 (<a href="/entry/600483">600483</a>), and FGFR1 (<a href="/entry/136350">136350</a>). The findings were consistent with a model in which KAL1 acts as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 7 probands with hypogonadotropic hypogonadism with or without anosmia (HH15; <a href="/entry/614880">614880</a>), <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified 5 heterozygous missense mutations (<a href="#0001">604846.0001</a>-<a href="#0005">604846.0005</a>). All of the HS6ST1 variants affected highly conserved residues, exhibited reduced activity compared to wildtype, and were not found in 500 controls or the SNP database. Because clinical variability was evident both within and across families carrying the same genetic variant, <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> analyzed 8 additional HH-associated genes to test whether other genetic factors were contributing to the observed variability, and identified heterozygous variants in the FGFR1 gene (<a href="/entry/136350#0025">136350.0025</a>) and in the NELF gene (<a href="/entry/608137#0001">608137.0001</a>) in 2 of the HH families, respectively. The authors concluded that the identified HS6ST1 missense mutations might not be sufficient to cause disease, and suggested that HS6ST1 represents an important gene contributing pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the HH family in which <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> had identified mutations in both the HS6ST1 (<a href="#0002">604846.0002</a>) and FGFR1 (<a href="/entry/136350#0025">136350.0025</a>) genes, <a href="#4" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> analyzed 7 genes involved in the FGF8 (<a href="/entry/600483">600483</a>)-FGFR1 (<a href="/entry/136350">136350</a>) network and identified additional mutations in 2 more genes, FGF17 (<a href="/entry/603725#0001">603725.0001</a>) and FLRT3 (<a href="/entry/604808#0001">604808.0001</a> and <a href="/entry/604808#0002">604808.0002</a>). <a href="#4" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21700882+23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 1 female and 2 male probands from 3 unrelated families with hypogonadotropic hypogonadism (HH15; <a href="/entry/614880">614880</a>), 1 with anosmia and 2 with a normal sense of smell, <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified heterozygosity for a 1114C-T transition in the HS6ST1 gene, resulting in an arg372-to-trp (R372W) substitution at a highly conserved residue. In vitro functional analysis demonstrated a 25 to 35% reduction in enzymatic activity with the R372W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R372W mutant displayed a reduced capacity to rescue a kal1 (<a href="/entry/300836">300836</a>)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. The female HH proband had absent puberty whereas the 2 male probands had partial puberty, and 1 male patient, who was anosmic, had osteoporosis, whereas the other male patient had osteopenia. In addition, the female proband had a brother with delayed puberty who did not carry the HS6ST1 R372W mutation, whereas the anosmic male proband had an unaffected brother who did carry the mutation. Analysis of 8 known HH-associated genes in these families revealed that the anosmic male proband carried an additional heterozygous missense mutation in the NELF gene (<a href="/entry/608137#0001">608137.0001</a>); no other mutations were identified. <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> concluded that mutations in HS6ST1 might not be sufficient to cause disease, but rather contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. <strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong> Nature 536: 285-291, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27535533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27535533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27535533[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature19057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27535533">Lek et al. (2016)</a> noted that this variant has a high allele frequency (0.0123) in the South Asian population in the ExAC database and that the database also reports 4 homozygotes for the variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27535533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs780352591 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs780352591;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/rs780352591?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=rs780352591" 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=rs780352591" 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=RCV000032892 OR RCV003546462" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032892, RCV003546462" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032892...</a>
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<p>In a 55-year-old woman with hypogonadotropic hypogonadism with anosmia (HH15; <a href="/entry/614880">614880</a>) from a large French Canadian pedigree with several consanguineous loops, previously reported by <a href="#6" class="mim-tip-reference" title="White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. <strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong> Am. J. Med. Genet. 15: 417-435, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881209</a>] [<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6881209">White et al. (1983)</a> and in which affected individuals displayed variable phenotypes, <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified homozygosity for an 886C-T transition in the HS6ST1 gene, resulting in an arg296-to-trp (R296W) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 50% reduction in enzymatic activity with the R296W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R296W mutant displayed a reduced capacity to rescue a kal1 (<a href="/entry/300836">300836</a>)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. Additional features in the proband included bilateral genu valgus and osteoporosis with multiple vertebral and tibial fractures. The proband's brother, who also had anosmic HH, was heterozygous for the R296W mutation, as was their unaffected father and 3 other family members, including 1 with anosmic HH, 1 with anosmic HH and cleft palate, and 1 unaffected individual. Other phenotypes among untested family members included normosmic HH in 1 individual and isolated cleft palate in 3. Analysis of 8 known HH-associated genes revealed that the proband, her brother, and their unaffected father all carried an additional heterozygous missense mutation in the FGFR1 gene (R250Q; <a href="/entry/136350#0025">136350.0025</a>), as did 2 other family members, 1 with anosmic HH and 1 with anosmic HH and cleft palate. The FGFR1 mutation was also found in heterozygosity in an unaffected family member who did not carry the R296W HS6ST1 mutation. No mutations were identified in the other HH-associated genes. <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> concluded that mutations in HS6ST1 might not be sufficient to cause disease, but rather contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21700882+6881209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the French Canadian pedigree in which <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> had identified mutations in both the FGFR1 and HS6ST1 genes, <a href="#4" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified additional mutations in 2 FGF-network genes, FGF17 (I108T; <a href="/entry/603725#0001">603725.0001</a>) and FLRT3 (E97G, <a href="/entry/604808#0001">604808.0001</a> and S144I, <a href="/entry/604808#0002">604808.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21700882+23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs201307896 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201307896;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/rs201307896?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=rs201307896" 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=rs201307896" 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=RCV000032893 OR RCV001852660 OR RCV002247411 OR RCV003952386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032893, RCV001852660, RCV002247411, RCV003952386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032893...</a>
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<p>In a 10.5-year-old boy with anosmic hypogonadotropic hypogonadism (HH15; <a href="/entry/614880">614880</a>), born of consanguineous parents, <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified heterozygosity for an 887G-A transition in the HS6ST1 gene, resulting in an arg296-to-gln (R296Q) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 15 to 30% reduction in enzymatic activity with the R296Q mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R296Q mutant displayed a reduced capacity to rescue a kal1 (<a href="/entry/300836">300836</a>)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. MRI at 11 months of age revealed a normal hypothalamic area and small pituitary, although the olfactory bulbs and nerves could not be assessed. The proband's mother, who had only delayed puberty and a normal sense of smell, was also heterozygous for the mutation. <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> proposed that mutations in HS6ST1 contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs761325768 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761325768;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/rs761325768?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=rs761325768" 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=rs761325768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 30-year-old man who was born with anosmic hypogonadotropic hypogonadism (HH15; <a href="/entry/614880">614880</a>), cleft palate, and bilateral genu valgus, <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified heterozygosity for a 938G-A transition in the HS6ST1 gene, resulting in an arg313-to-gln (R313Q) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 30% reduction in enzymatic activity with the R313Q mutant compared to wildtype when HS was the acceptor substrate, whereas mutant activity was similar to wildtype when completely desulfated re-N-sulfated heparin was used as the substrate. In an in vivo assay involving C. elegans, the R313Q mutant displayed a reduced capacity to rescue a kal1 (<a href="/entry/300836">300836</a>)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. MRI in the proband showed absent olfactory bulbs and a normal pituitary. The proband's father, who had only delayed puberty, and an asymptomatic, fertile sister were both also heterozygous for the mutation, whereas another sister with anosmia did not carry the mutation. In addition, the paternal grandmother had delayed puberty, and the paternal grandfather was anosmic. <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> proposed that mutations in HS6ST1 contribute to HH via oligogenic interactions with other genes in the genetic network responsible for human reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2104908342 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2104908342;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=rs2104908342" 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=rs2104908342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 36-year-old man who had anosmic hypogonadotropic hypogonadism (HH15; <a href="/entry/614880">614880</a>), <a href="#5" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified heterozygosity for a 1180A-G transition in the HS6ST1 gene, resulting in a met394-to-val (M394V) substitution at a highly conserved residue. In vitro functional analysis demonstrated a 30 to 70% reduction in enzymatic activity with the M394V mutant compared to wildtype, and in an in vivo assay involving C. elegans, the M394V mutant displayed a reduced capacity to rescue a kal1 (<a href="/entry/300836">300836</a>)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. At 21 years of age, the proband presented for failure to undergo puberty. He was overweight and eunuchoidal, with Tanner II pubic hair and small testes, and had severe bilateral genu valgus. While the patient was on replacement testosterone therapy, his wife conceived. Later, he was found to have a normal adult serum testosterone level and normal sperm count after having discontinued his replacement therapy, indicating reversal of his GnRH-deficiency HH. Fourteen years later, repeat neuroendocrine evaluation confirmed a sustained reversal of his GnRH deficiency; MRI scan showed absent olfactory bulbs and a small pituitary gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Molecular characterization and expression of heparan-sulfate 6-sulfotransferase: complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells.</strong>
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J. Biol. Chem. 273: 9208-9213, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535912</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9535912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.15.9208" target="_blank">Full Text</a>]
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Habuchi, H., Tanaka, M., Habuchi, O., Yoshida, K., Suzuki, H., Ban, K., Kimata, K.
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<strong>The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine.</strong>
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J. Biol. Chem. 275: 2859-2868, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.275.4.2859" target="_blank">Full Text</a>]
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Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others.
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<strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong>
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Nature 536: 285-291, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27535533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27535533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27535533[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=27535533" 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/nature19057" target="_blank">Full Text</a>]
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Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others.
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<strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong>
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Am. J. Hum. Genet. 92: 725-743, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[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=23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E.
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<strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong>
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Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1102284108" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="White1983" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W.
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<strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong>
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Am. J. Med. Genet. 15: 417-435, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881209</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6881209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 12/01/2016
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/05/2013<br>Marla J. F. O'Neill - updated : 10/17/2012<br>Patricia A. Hartz - updated : 5/4/2005
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</span>
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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="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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<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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Patti M. Sherman : 4/17/2000
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</span>
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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 : 12/01/2016
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</span>
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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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alopez : 06/05/2013<br>carol : 10/17/2012<br>mgross : 6/7/2005<br>terry : 5/4/2005<br>mcapotos : 5/1/2000<br>psherman : 4/18/2000
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604846
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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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HEPARAN SULFATE 6-O-SULFOTRANSFERASE 1; HS6ST1
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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HS6ST
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HS6ST1</em></strong>
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</span>
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</p>
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<strong>
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<em>
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Cytogenetic location: 2q14.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:128,265,480-128,318,868 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</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>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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2q14.3
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</td>
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<td>
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<span class="mim-font">
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{Hypogonadotropic hypogonadism 15 with or without anosmia}
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</span>
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</td>
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<td>
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<span class="mim-font">
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614880
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Heparan sulfate (HS) 6-O-sulfotransferase catalyzes the transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate to position 6 of the N-sulfoglucosamine residue of heparan sulfate (Habuchi et al., 1998). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By screening a human fetal brain cDNA library with a Chinese hamster Hs6st cDNA, Habuchi et al. (1998) isolated human HS6ST cDNAs. The predicted 401-amino acid human HS6ST protein is a type II transmembrane protein, with an N-terminal transmembrane domain. A putative cleavage site occurs near the C-terminal end of the transmembrane domain. HS6ST contains 2 potential N-glycosylation sites. It does not share significant sequence similarity to other known sulfotransferases, including HS2ST. HS6ST does not contain a conserved 3-prime-phosphoadenosine 5-prime-phosphosulfate-binding site sequence, or a 'P-loop,' which is found in most sulfotransferases and has been implicated as an ATP- or GTP-binding site. Northern blot analysis of human fetal brain RNA detected a 3.9-kb HS6ST transcript. </p><p>Habuchi et al. (2000) cloned Hs6st1 from a mouse brain cDNA library. The deduced 401-amino acid protein has characteristics of a type II transmembrane protein, with a short N-terminal segment followed by a hydrophobic sequence. It also contains 2 N-glycosylation sites. Northern blot analysis detected a 3.9-kb Hs6st1 transcript in most mouse tissues examined, with predominant expression in liver. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The International Radiation Hybrid Mapping Consortium mapped the HS6ST1 gene to chromosome 2 (RH78052).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Habuchi et al. (1998) found that recombinant HS6ST expressed in mammalian cells exhibited HS6ST activity. </p><p>Habuchi et al. (2000) demonstrated elevated 6-O-sulfotransferase activity in the cytoplasm of COS-7 cells transfected with mouse Hs6st1. Hs6st1 was also secreted into the medium. Hs6st1 showed 6-O-sulfotransferase activity against HS, N-sulfated heparosan, heparin, and some HS derivatives. It did not show sulfotransferase activity toward other glycosaminoglycans examined. </p><p>In experiments in C. elegans, Tornberg et al. (2011) observed that HS cell-specifically regulates neural branching in vivo in concert with other genes that are associated with hypogonadotropic hypogonadism (see 147950), including KAL1 (300836), FGF8 (600483), and FGFR1 (136350). The findings were consistent with a model in which KAL1 acts as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner. </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>In 7 probands with hypogonadotropic hypogonadism with or without anosmia (HH15; 614880), Tornberg et al. (2011) identified 5 heterozygous missense mutations (604846.0001-604846.0005). All of the HS6ST1 variants affected highly conserved residues, exhibited reduced activity compared to wildtype, and were not found in 500 controls or the SNP database. Because clinical variability was evident both within and across families carrying the same genetic variant, Tornberg et al. (2011) analyzed 8 additional HH-associated genes to test whether other genetic factors were contributing to the observed variability, and identified heterozygous variants in the FGFR1 gene (136350.0025) and in the NELF gene (608137.0001) in 2 of the HH families, respectively. The authors concluded that the identified HS6ST1 missense mutations might not be sufficient to cause disease, and suggested that HS6ST1 represents an important gene contributing pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction. </p><p>In the HH family in which Tornberg et al. (2011) had identified mutations in both the HS6ST1 (604846.0002) and FGFR1 (136350.0025) genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified additional mutations in 2 more genes, FGF17 (603725.0001) and FLRT3 (604808.0001 and 604808.0002). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>5 Selected Examples):</strong>
|
|
</span>
|
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</h4>
|
|
<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>
|
|
<span class="mim-font">
|
|
<strong>.0001 HYPOGONADOTROPIC HYPOGONADISM 15 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO</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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HS6ST1, ARG372TRP
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<br />
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SNP: rs199538589,
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gnomAD: rs199538589,
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ClinVar: RCV000032891, RCV000156968, RCV000455725, RCV001258243, RCV001358502, RCV003917537
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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 1 female and 2 male probands from 3 unrelated families with hypogonadotropic hypogonadism (HH15; 614880), 1 with anosmia and 2 with a normal sense of smell, Tornberg et al. (2011) identified heterozygosity for a 1114C-T transition in the HS6ST1 gene, resulting in an arg372-to-trp (R372W) substitution at a highly conserved residue. In vitro functional analysis demonstrated a 25 to 35% reduction in enzymatic activity with the R372W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R372W mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. The female HH proband had absent puberty whereas the 2 male probands had partial puberty, and 1 male patient, who was anosmic, had osteoporosis, whereas the other male patient had osteopenia. In addition, the female proband had a brother with delayed puberty who did not carry the HS6ST1 R372W mutation, whereas the anosmic male proband had an unaffected brother who did carry the mutation. Analysis of 8 known HH-associated genes in these families revealed that the anosmic male proband carried an additional heterozygous missense mutation in the NELF gene (608137.0001); no other mutations were identified. Tornberg et al. (2011) concluded that mutations in HS6ST1 might not be sufficient to cause disease, but rather contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction. </p><p>Lek et al. (2016) noted that this variant has a high allele frequency (0.0123) in the South Asian population in the ExAC database and that the database also reports 4 homozygotes for the variant. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0002 HYPOGONADOTROPIC HYPOGONADISM 15 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HS6ST1, ARG296TRP
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<br />
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|
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SNP: rs780352591,
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gnomAD: rs780352591,
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ClinVar: RCV000032892, RCV003546462
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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 55-year-old woman with hypogonadotropic hypogonadism with anosmia (HH15; 614880) from a large French Canadian pedigree with several consanguineous loops, previously reported by White et al. (1983) and in which affected individuals displayed variable phenotypes, Tornberg et al. (2011) identified homozygosity for an 886C-T transition in the HS6ST1 gene, resulting in an arg296-to-trp (R296W) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 50% reduction in enzymatic activity with the R296W mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R296W mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. Additional features in the proband included bilateral genu valgus and osteoporosis with multiple vertebral and tibial fractures. The proband's brother, who also had anosmic HH, was heterozygous for the R296W mutation, as was their unaffected father and 3 other family members, including 1 with anosmic HH, 1 with anosmic HH and cleft palate, and 1 unaffected individual. Other phenotypes among untested family members included normosmic HH in 1 individual and isolated cleft palate in 3. Analysis of 8 known HH-associated genes revealed that the proband, her brother, and their unaffected father all carried an additional heterozygous missense mutation in the FGFR1 gene (R250Q; 136350.0025), as did 2 other family members, 1 with anosmic HH and 1 with anosmic HH and cleft palate. The FGFR1 mutation was also found in heterozygosity in an unaffected family member who did not carry the R296W HS6ST1 mutation. No mutations were identified in the other HH-associated genes. Tornberg et al. (2011) concluded that mutations in HS6ST1 might not be sufficient to cause disease, but rather contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction. </p><p>In the French Canadian pedigree in which Tornberg et al. (2011) had identified mutations in both the FGFR1 and HS6ST1 genes, Miraoui et al. (2013) identified additional mutations in 2 FGF-network genes, FGF17 (I108T; 603725.0001) and FLRT3 (E97G, 604808.0001 and S144I, 604808.0002). </p>
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<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 15 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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HS6ST1, ARG296GLN
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SNP: rs201307896,
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gnomAD: rs201307896,
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ClinVar: RCV000032893, RCV001852660, RCV002247411, RCV003952386
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<p>In a 10.5-year-old boy with anosmic hypogonadotropic hypogonadism (HH15; 614880), born of consanguineous parents, Tornberg et al. (2011) identified heterozygosity for an 887G-A transition in the HS6ST1 gene, resulting in an arg296-to-gln (R296Q) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 15 to 30% reduction in enzymatic activity with the R296Q mutant compared to wildtype, and in an in vivo assay involving C. elegans, the R296Q mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. MRI at 11 months of age revealed a normal hypothalamic area and small pituitary, although the olfactory bulbs and nerves could not be assessed. The proband's mother, who had only delayed puberty and a normal sense of smell, was also heterozygous for the mutation. Tornberg et al. (2011) proposed that mutations in HS6ST1 contribute to HH via oligogenic interactions with other genes in the genetic network responsible for neuroendocrine control of human reproduction. </p>
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<span class="mim-font">
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<strong>.0004 HYPOGONADOTROPIC HYPOGONADISM 15 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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HS6ST1, ARG313GLN
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SNP: rs761325768,
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gnomAD: rs761325768,
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ClinVar: RCV000032894
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<p>In a 30-year-old man who was born with anosmic hypogonadotropic hypogonadism (HH15; 614880), cleft palate, and bilateral genu valgus, Tornberg et al. (2011) identified heterozygosity for a 938G-A transition in the HS6ST1 gene, resulting in an arg313-to-gln (R313Q) substitution at a highly conserved residue. In vitro functional analysis demonstrated an approximately 30% reduction in enzymatic activity with the R313Q mutant compared to wildtype when HS was the acceptor substrate, whereas mutant activity was similar to wildtype when completely desulfated re-N-sulfated heparin was used as the substrate. In an in vivo assay involving C. elegans, the R313Q mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. MRI in the proband showed absent olfactory bulbs and a normal pituitary. The proband's father, who had only delayed puberty, and an asymptomatic, fertile sister were both also heterozygous for the mutation, whereas another sister with anosmia did not carry the mutation. In addition, the paternal grandmother had delayed puberty, and the paternal grandfather was anosmic. Tornberg et al. (2011) proposed that mutations in HS6ST1 contribute to HH via oligogenic interactions with other genes in the genetic network responsible for human reproduction. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 HYPOGONADOTROPIC HYPOGONADISM 15 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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HS6ST1, MET394VAL
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SNP: rs2104908342,
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ClinVar: RCV000032895
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<p>In a 36-year-old man who had anosmic hypogonadotropic hypogonadism (HH15; 614880), Tornberg et al. (2011) identified heterozygosity for a 1180A-G transition in the HS6ST1 gene, resulting in a met394-to-val (M394V) substitution at a highly conserved residue. In vitro functional analysis demonstrated a 30 to 70% reduction in enzymatic activity with the M394V mutant compared to wildtype, and in an in vivo assay involving C. elegans, the M394V mutant displayed a reduced capacity to rescue a kal1 (300836)-dependent axon branching phenotype compared to wildtype HS6ST1. The mutation was not found in the SNP database or in 500 ethnically and age-matched controls. At 21 years of age, the proband presented for failure to undergo puberty. He was overweight and eunuchoidal, with Tanner II pubic hair and small testes, and had severe bilateral genu valgus. While the patient was on replacement testosterone therapy, his wife conceived. Later, he was found to have a normal adult serum testosterone level and normal sperm count after having discontinued his replacement therapy, indicating reversal of his GnRH-deficiency HH. Fourteen years later, repeat neuroendocrine evaluation confirmed a sustained reversal of his GnRH deficiency; MRI scan showed absent olfactory bulbs and a small pituitary gland. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Habuchi, H., Kobayashi, M., Kimata, K.
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<strong>Molecular characterization and expression of heparan-sulfate 6-sulfotransferase: complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells.</strong>
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J. Biol. Chem. 273: 9208-9213, 1998.
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[PubMed: 9535912]
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[Full Text: https://doi.org/10.1074/jbc.273.15.9208]
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Habuchi, H., Tanaka, M., Habuchi, O., Yoshida, K., Suzuki, H., Ban, K., Kimata, K.
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<strong>The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine.</strong>
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J. Biol. Chem. 275: 2859-2868, 2000.
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[PubMed: 10644753]
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[Full Text: https://doi.org/10.1074/jbc.275.4.2859]
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Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others.
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<strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong>
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Nature 536: 285-291, 2016.
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[PubMed: 27535533]
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[Full Text: https://doi.org/10.1038/nature19057]
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<p class="mim-text-font">
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Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others.
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<strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong>
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Am. J. Hum. Genet. 92: 725-743, 2013.
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[PubMed: 23643382]
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[Full Text: https://doi.org/10.1016/j.ajhg.2013.04.008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E.
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<strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong>
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Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.
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[PubMed: 21700882]
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[Full Text: https://doi.org/10.1073/pnas.1102284108]
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</p>
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<p class="mim-text-font">
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White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W.
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<strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong>
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Am. J. Med. Genet. 15: 417-435, 1983.
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[PubMed: 6881209]
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[Full Text: https://doi.org/10.1002/ajmg.1320150307]
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Ada Hamosh - updated : 12/01/2016<br>Marla J. F. O'Neill - updated : 06/05/2013<br>Marla J. F. O'Neill - updated : 10/17/2012<br>Patricia A. Hartz - updated : 5/4/2005
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Patti M. Sherman : 4/17/2000
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carol : 12/01/2016<br>alopez : 06/05/2013<br>carol : 10/17/2012<br>mgross : 6/7/2005<br>terry : 5/4/2005<br>mcapotos : 5/1/2000<br>psherman : 4/18/2000
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