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Entry
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- *313700 - ANDROGEN RECEPTOR; AR
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*313700</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/313700">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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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=ENSG00000169083;t=ENST00000374690" 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=367" 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=313700" 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=ENSG00000169083;t=ENST00000374690" 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_000044,NM_001011645,NM_001348061,NM_001348063,NM_001348064" 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_000044" 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=313700" 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=02437&isoform_id=02437_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/AR" 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/178628,178656,178872,178882,178892,178894,178906,179026,179034,460281,642484,4378961,5639999,6118054,8176541,8176542,12958717,12958719,12958721,12958723,21322252,25990332,58535455,119625785,124375976,224181614,224181616,224181618,224181620,224181622,270358642,302028369,325495457,475797201,566814319,566814321,566814323,608785149,1018618719,1143076912,1143076917,1143076919,1493511996,1829009150,1829009180,1829009182,1829009184" 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/P10275" 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=367" 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=ENSG00000169083;t=ENST00000374690" 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=AR" 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=AR" 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+367" 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/AR" 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:367" 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/367" 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=chrX&hgg_gene=ENST00000374690.9&hgg_start=67544021&hgg_end=67730619&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:644" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:644" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/ar" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=313700[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=313700[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/AR/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000169083" 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=AR" 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=AR" 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=AR" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://androgendb.mcgill.ca/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Androgen Receptor</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/AR" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">AR database at LOVD</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=AR&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/PA57" 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:644" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88064" 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/AR#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:88064" 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/367/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA000991/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=367" 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://zfin.org/ZDB-GENE-060131-1" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:313700" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:367" 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=AR&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 122811000119101, 12313004, 230253001, 368851000119102<br />
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<strong>ICD10CM:</strong> E34.5, E34.50, E34.51, E34.52<br />
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<strong>ICD9CM:</strong> 259.5, 259.51, 259.52<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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313700
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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>
|
|
<span class="mim-font">
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ANDROGEN RECEPTOR; AR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
DIHYDROTESTOSTERONE RECEPTOR; DHTR<br />
|
|
NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 4; NR3C4
|
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</span>
|
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</h4>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=AR" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AR</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">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/378?start=-3&limit=10&highlight=378">Xq12</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:67544021-67730619&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'})">X:67,544,021-67,730,619</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
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|
|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
|
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Phenotype
|
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Xq12
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{Prostate cancer, susceptibility to}
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Androgen insensitivity
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Androgen insensitivity, partial, with or without breast cancer
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<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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<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.">
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<p>The gene encoding androgen receptor (AR), alternatively known as the dihydrotestosterone receptor, is located on the X chromosome. It is mutant in the androgen insensitivity syndrome (AIS; <a href="/entry/300068">300068</a>), formerly known as the testicular feminization syndrome (TFM), and in Kennedy spinal and bulbar muscular atrophy (SBMA; <a href="/entry/313200">313200</a>). Clinical variants of the androgen insensitivity syndrome (partial androgen insensitivity) include the Reifenstein syndrome (<a href="/entry/312300">312300</a>).</p><p>The AR protein belongs to the class of nuclear receptors called activated class I steroid receptors, which also includes glucocorticoid receptor (GCCR; <a href="/entry/138040">138040</a>), progesterone receptor (PGR; <a href="/entry/607311">607311</a>), and mineralocorticoid receptor (NR3C2; <a href="/entry/600983">600983</a>). These receptors recognize canonical androgen response elements (AREs), which are inverted repeats of 5-prime-TGTTCT-3-prime. The major domains of AR include N- and C-terminal activation domains, which are designated activation function-1 (AF-1) and AF-2, a ligand-binding domain, and a polyglutamine tract (<a href="#21" class="mim-tip-reference" title="Callewaert, L., Christiaens, V., Haelens, A., Verrijdt, G., Verhoeven, G., Claessens, F. <strong>Implications of a polyglutamine tract in the function of the human androgen receptor.</strong> Biochem. Biophys. Res. Commun. 306: 46-52, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788064</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00902-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788064">Callewaert et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788064" 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="#27" class="mim-tip-reference" title="Chang, C., Kokontis, J., Liao, S. <strong>Molecular cloning of human and rat complementary DNA encoding androgen receptors.</strong> Science 240: 324-326, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3353726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3353726</a>] [<a href="https://doi.org/10.1126/science.3353726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3353726">Chang et al. (1988)</a> and <a href="#100" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sar, M., Tan, J., Higgs, H. N., Larson, R. E., French, F. S., Wilson, E. M. <strong>The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate.</strong> Molec. Endocr. 2: 1265-1275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3216866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3216866</a>] [<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3216866">Lubahn et al. (1988)</a> cloned human androgen receptor cDNAs. <a href="#100" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sar, M., Tan, J., Higgs, H. N., Larson, R. E., French, F. S., Wilson, E. M. <strong>The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate.</strong> Molec. Endocr. 2: 1265-1275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3216866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3216866</a>] [<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3216866">Lubahn et al. (1988)</a> determined the complete coding sequence of the human androgen receptor and compared the deduced 919-amino acid sequence (98,999 Da) to the 902-amino acid sequence of rat AR (98,227 Da). Identical sequences were found in the DNA- and hormone-binding domains, with an overall homology of 85%. <a href="#27" class="mim-tip-reference" title="Chang, C., Kokontis, J., Liao, S. <strong>Molecular cloning of human and rat complementary DNA encoding androgen receptors.</strong> Science 240: 324-326, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3353726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3353726</a>] [<a href="https://doi.org/10.1126/science.3353726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3353726">Chang et al. (1988)</a> obtained cDNAs from human testis and rat ventral prostate cDNA libraries. The deduced amino acid sequence indicated the presence of a cysteine-rich DNA-binding domain that is highly conserved in all steroid receptors. The human cDNA was transcribed and the RNA product translated in cell-free systems to yield a 76-kD protein. The protein was immunoprecipitable by human autoimmune antibodies to the androgen receptor, and it bound androgens specifically and with high affinity. (Some older men with prostate cancer have high titers of autoimmune antibodies to androgen receptor (<a href="#93" class="mim-tip-reference" title="Liao, S., Witte, D. <strong>Autoimmune anti-androgen-receptor antibodies in human serum.</strong> Proc. Nat. Acad. Sci. 82: 8345-8348, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3866227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3866227</a>] [<a href="https://doi.org/10.1073/pnas.82.24.8345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3866227">Liao and Witte, 1985</a>).) Both <a href="#27" class="mim-tip-reference" title="Chang, C., Kokontis, J., Liao, S. <strong>Molecular cloning of human and rat complementary DNA encoding androgen receptors.</strong> Science 240: 324-326, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3353726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3353726</a>] [<a href="https://doi.org/10.1126/science.3353726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3353726">Chang et al. (1988)</a> and <a href="#100" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sar, M., Tan, J., Higgs, H. N., Larson, R. E., French, F. S., Wilson, E. M. <strong>The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate.</strong> Molec. Endocr. 2: 1265-1275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3216866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3216866</a>] [<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3216866">Lubahn et al. (1988)</a> used AR as the symbol for androgen receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3353726+3866227+3216866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains. The N-terminal domain, which serves a modulatory function, is encoded by exon 1 (1,586 bp). The DNA-binding domain is encoded by exons 2 and 3 (152 and 117 bp, respectively). The androgen-binding domain is encoded by 5 exons which vary from 131 to 288 bp in size.</p><p>In human prostate, the major AR mRNA species is 10 kb, whereas a less abundant mRNA is approximately 7 kb (<a href="#100" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sar, M., Tan, J., Higgs, H. N., Larson, R. E., French, F. S., Wilson, E. M. <strong>The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate.</strong> Molec. Endocr. 2: 1265-1275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3216866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3216866</a>] [<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3216866">Lubahn et al., 1988</a>). In the prostate, AR is localized predominantly to nuclei of granular epithelial cells. <a href="#171" class="mim-tip-reference" title="Tilley, W. D., Marcelli, M., Wilson, J. D., McPhaul, M. J. <strong>Characterization and expression of a cDNA encoding the human androgen receptor.</strong> Proc. Nat. Acad. Sci. 86: 327-331, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2911578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2911578</a>] [<a href="https://doi.org/10.1073/pnas.86.1.327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2911578">Tilley et al. (1989)</a> isolated a cDNA that encodes the complete human AR gene. The cDNA predicted a protein of 917 amino acids with a molecular mass of of 98,918 Da. Introduction of the cDNA into heterologous mammalian cells caused expression of high levels of a protein that binds dihydrotestosterone with the affinity, specificity, and sedimentation properties characteristic of the native receptor. Comparison with the amino acid sequence of previously cloned steroid hormone receptors showed a high degree of sequence conservation with the progesterone, glucocorticoid, and mineralocorticoid receptors in the putative hormone and DNA-binding domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2911578+3216866" 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>Two naturally occurring hormone-binding forms of progesterone receptor (<a href="/entry/607311">607311</a>) have been identified. The A isoform is an N-terminally truncated version of the full-length B isoform. Several lines of evidence suggest that the 2 isoforms serve specific functions. <a href="#188" class="mim-tip-reference" title="Wilson, C. M., McPhaul, M. J. <strong>A and B forms of the androgen receptor are present in human genital skin fibroblasts.</strong> Proc. Nat. Acad. Sci. 91: 1234-1238, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8108393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8108393</a>] [<a href="https://doi.org/10.1073/pnas.91.4.1234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8108393">Wilson and McPhaul (1994)</a> demonstrated 2 forms of the androgen receptor protein in human genital skin fibroblasts. The apparent molecular masses were approximately 110 kD and 87 kD. The 87-kD isoform (AR-A) contained an intact C terminus but lacked the normal N terminus found in the 110-kD isoform (AR-B). AR-A is the same size as the mutant form of AR produced in fibroblasts from an androgen-resistant individual by initiation of AR synthesis at the first internal met188 residue of AR-B, as reported by <a href="#203" class="mim-tip-reference" title="Zoppi, S., Wilson, C. M., Harbison, M. D., Griffin, J. E., Wilson, J. D., McPhaul, M. J., Marcelli, M. <strong>Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation.</strong> J. Clin. Invest. 91: 1105-1112, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8450040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8450040</a>] [<a href="https://doi.org/10.1172/JCI116269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8450040">Zoppi et al. (1993)</a>. The AR isoforms resembled the A and B forms of the progesterone receptor, which also are encoded by a single gene and differ by the absence or presence of an N-terminal segment. The A and B forms of the progesterone receptor differ in their ability to activate target genes and are regulated differently in various types of cells. The identification of similar forms of AR raised the possibility that the 2 isoforms also serve different functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8108393+8450040" 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="#72" class="mim-tip-reference" title="Kang, H.-Y., Yeh, S., Fujimoto, N., Chang, C. <strong>Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor.</strong> J. Biol. Chem. 274: 8570-8576, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10085091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10085091</a>] [<a href="https://doi.org/10.1074/jbc.274.13.8570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10085091">Kang et al. (1999)</a> demonstrated that the ARA54 gene (RNF14; <a href="/entry/605675">605675</a>) can function as a coactivator for androgen-dependent transcription on both wildtype and mutant androgen receptor. In the presence of a certain amount of 17-beta-estradiol or hydroxyflutamide, the transcriptional activity of a specific AR mutant was significantly enhanced, whereas that of wildtype and another AR mutant was not. They therefore suggested that both ARA54 and the positions of the AR mutation might contribute to the specificity of AR-mediated transactivation. Coexpression of ARA54 with other AR coactivators, such as ARA70 (NCOA4; <a href="/entry/601984">601984</a>) and SRC1 (NCOA1; <a href="/entry/602691">602691</a>), showed additive stimulation of AR-mediated transactivation, indicating that these cofactors may function individually as AR coactivators to induce AR target gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10085091" 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="#163" class="mim-tip-reference" title="Sullivan, D. A., Sullivan, B. D., Ullman, M. D., Rocha, E. M., Krenzer, K. L., Cermak, J. M., Toda, I., Doane, M. G., Evans, J. E., Wickham, L. A. <strong>Androgen influence on the meibomian gland.</strong> Invest. Ophthal. Vis. Sci. 41: 3732-3742, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11053270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11053270</a>]" pmid="11053270">Sullivan et al. (2000)</a> demonstrated that the androgen receptor protein exists within acinar epithelial cell nuclei of the rat meibomian gland. In studies in rats and rabbits, they found evidence that the meibomian gland is an androgen target organ and that androgens influence the lipid profile within this tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11053270" 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="#159" class="mim-tip-reference" title="Shang, Y., Myers, M., Brown, M. <strong>Formation of the androgen receptor transcription complex.</strong> Molec. Cell 9: 601-610, 2002. Note: Erratum: Molec. Cell 11: 1697 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11931767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11931767</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00471-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11931767">Shang et al. (2002)</a> described distinct functions for cofactor proteins and gene regulatory elements in the assembly of AR-mediated transcription complexes. The formation of an activation complex involves AR, coactivators, and RNA polymerase II (pol II; see <a href="/entry/180660">180660</a>) recruitment to both the enhancer and promoter, whereas the formation of a repression complex involves factors bound only at the promoter and not the enhancer. The results suggested a model for the functional coordination between the promoter and enhancer in which communication between these elements is established through shared coactivators in the AR transcription complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11931767" 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="#91" class="mim-tip-reference" title="Lee, D. K., Li, M., Chang, C. <strong>The second largest subunit of RNA polymerase II interacts with and enhances transactivation of androgen receptor.</strong> Biochem. Biophys. Res. Commun. 302: 162-169, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12593864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12593864</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00126-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12593864">Lee et al. (2003)</a> hypothesized that AR may modulate gene expression by enhancing the efficiency of transcriptional elongation. They demonstrated that coexpression of the second largest subunit of RNA polymerase II, RPB2 (POLR2B; <a href="/entry/180661">180661</a>), enhanced AR transactivation. Coexpression with other RNA polymerase II subunits or TFIIB (GTF2B; <a href="/entry/189963">189963</a>) did not enhance AR-mediated transcription. <a href="#91" class="mim-tip-reference" title="Lee, D. K., Li, M., Chang, C. <strong>The second largest subunit of RNA polymerase II interacts with and enhances transactivation of androgen receptor.</strong> Biochem. Biophys. Res. Commun. 302: 162-169, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12593864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12593864</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00126-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12593864">Lee et al. (2003)</a> concluded that AR may interact with TFIIH (see <a href="/entry/189968">189968</a>), P-TEFb (see CCNT2; <a href="/entry/603862">603862</a>), and RPB2 to enhance transcription from AR target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12593864" 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="#121" class="mim-tip-reference" title="Metzger, E., Muller, J. M., Ferrari, S., Buettner, R., Schule, R. <strong>A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer.</strong> EMBO J. 22: 270-280, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514133</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12514133[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/10.1093/emboj/cdg023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514133">Metzger et al. (2003)</a> found that AR and PRK1 (PRKCL1; <a href="/entry/601032">601032</a>) interacted in vitro and in vivo. Stimulation of the PRK1 signaling cascade resulted in ligand-dependent superactivation of AR in human prostate carcinoma cells, and PRK1 promoted a functional complex of AR with the coactivator TIF2 (NCOA2; <a href="/entry/601993">601993</a>). PRK1 signaling stimulated AR activity in the presence of adrenal androgens and in the presence of an AR antagonist. <a href="#121" class="mim-tip-reference" title="Metzger, E., Muller, J. M., Ferrari, S., Buettner, R., Schule, R. <strong>A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer.</strong> EMBO J. 22: 270-280, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514133</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12514133[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/10.1093/emboj/cdg023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514133">Metzger et al. (2003)</a> concluded that AR is controlled by PRK1 signaling as well as by ligand binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12514133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Callewaert, L., Christiaens, V., Haelens, A., Verrijdt, G., Verhoeven, G., Claessens, F. <strong>Implications of a polyglutamine tract in the function of the human androgen receptor.</strong> Biochem. Biophys. Res. Commun. 306: 46-52, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788064</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00902-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788064">Callewaert et al. (2003)</a> found that deletion of the polyglutamine tract within the N-terminal domain of AR increased transactivation of the receptor through canonical AREs, and the effect appeared due to tighter interaction between the N- and C-terminal domains of AR. Deletion of the polyglutamine tract also increased recruitment of SRC1 to the N-terminal domain of AR. Transactivation of selective AREs, which contain direct rather than inverted repeats of 5-prime-TGTTCT-3-prime, were not influenced by deletion of the AR polyglutamine tract. <a href="#21" class="mim-tip-reference" title="Callewaert, L., Christiaens, V., Haelens, A., Verrijdt, G., Verhoeven, G., Claessens, F. <strong>Implications of a polyglutamine tract in the function of the human androgen receptor.</strong> Biochem. Biophys. Res. Commun. 306: 46-52, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788064</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)00902-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788064">Callewaert et al. (2003)</a> hypothesized that AR transcriptional activity on selective AREs does not depend on interaction between the N- and C-terminal domains of AR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using microarray analysis of rat ventral prostate RNA following 5-alpha-dihydrotestosterone treatment, <a href="#132" class="mim-tip-reference" title="Nantermet, P. V., Xu, J., Yu, Y., Hodor, P., Holder, D., Adamski, S., Gentile, M. A., Kimmel, D. B., Harada, S., Gerhold, D., Freedman, L. P., Ray, W. J. <strong>Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland.</strong> J. Biol. Chem. 279: 1310-1322, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14576152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14576152</a>] [<a href="https://doi.org/10.1074/jbc.M310206200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14576152">Nantermet et al. (2004)</a> found that AR rapidly modulated the expression of genes involved in proliferation and differentiation. AR repressed expression of several key cell cycle inhibitors while modulating members of the Wnt (see <a href="/entry/164820">164820</a>) and Notch (see <a href="/entry/190198">190198</a>) signaling pathways, multiple growth factors, peptide hormone signaling systems, and genes involved in MAP kinase and calcium signaling. The data suggested that activity of p53 (<a href="/entry/191170">191170</a>) was negatively regulated by AR activation, even though p53 RNA was unchanged. Using LNCaP cells, <a href="#132" class="mim-tip-reference" title="Nantermet, P. V., Xu, J., Yu, Y., Hodor, P., Holder, D., Adamski, S., Gentile, M. A., Kimmel, D. B., Harada, S., Gerhold, D., Freedman, L. P., Ray, W. J. <strong>Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland.</strong> J. Biol. Chem. 279: 1310-1322, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14576152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14576152</a>] [<a href="https://doi.org/10.1074/jbc.M310206200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14576152">Nantermet et al. (2004)</a> determined that AR inhibited p53 protein accumulation in the nucleus, providing a posttranscriptional mechanism by which androgens control prostate cell growth and survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14576152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By SDS-PAGE and peptide mass fingerprinting, <a href="#69" class="mim-tip-reference" title="Ishitani, K., Yoshida, T., Kitagawa, H., Ohta, H., Nozawa, S., Kato, S. <strong>p54(nrb) acts as a transcriptional coactivator for activation function 1 of the human androgen receptor.</strong> Biochem. Biophys. Res. Commun. 306: 660-665, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12810069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12810069</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)01021-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12810069">Ishitani et al. (2003)</a> characterized human embryonic kidney cell nuclear proteins that interacted with purified AF-1 of AR. Proteins that interacted with AF-1 included nuclear RNA-binding protein NRB54 (NONO; <a href="/entry/300084">300084</a>), polypyrimidine tract-binding protein-associated splicing factor (PSF, or SFPQ; <a href="/entry/605199">605199</a>), paraspeckle protein-1 (PSP1, or PSPC1; <a href="/entry/612408">612408</a>), and PSP2 (RBM14; <a href="/entry/612409">612409</a>), which are assumed to be involved in pre-mRNA processing. Binding of NRB54 to AF-1 was ligand dependent, and AF-1 function was potentiated by NRB54. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12810069" 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="#90" class="mim-tip-reference" title="Lee, D. K., Chang, C. <strong>Expression and degradation of androgen receptor: mechanism and clinical implication.</strong> J. Clin. Endocr. Metab. 88: 4043-4054, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970260</a>] [<a href="https://doi.org/10.1210/jc.2003-030261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12970260">Lee and Chang (2003)</a> reviewed mechanisms implicated in the control of AR protein expression and degradation and their potential relationship to androgen-related diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12970260" 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="#106" class="mim-tip-reference" title="Mandrusiak, L. M., Beitel, L. K., Wang, X., Scanlon, T. C., Chevalier-Larsen, E., Merry, D. E., Trifiro, M. A. <strong>Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor.</strong> Hum. Molec. Genet. 12: 1497-1506, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812978</a>] [<a href="https://doi.org/10.1093/hmg/ddg161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812978">Mandrusiak et al. (2003)</a> found that androgen receptor N-terminal fragments are a substrate for transglutaminase (see <a href="/entry/190195">190195</a>). Western blots of the proteins following incubation with transglutaminase showed loss of several different epitopes of the AR, suggestive of transglutaminase crosslinking of the AR, which interferes with antibody recognition. HEK GFPu-1 cells expressing polyglutamine-expanded androgen receptor and transglutaminase exhibited ligand-dependent proteasome dysfunction; this effect was not observed in the presence of cystamine, a transglutaminase inhibitor. In addition, transglutaminase-mediated isopeptide bonds were detected in brains of SBMA transgenic mice, but not in controls, suggesting involvement of transglutaminase-catalyzed reactions in polyglutamine disease pathogenesis. <a href="#106" class="mim-tip-reference" title="Mandrusiak, L. M., Beitel, L. K., Wang, X., Scanlon, T. C., Chevalier-Larsen, E., Merry, D. E., Trifiro, M. A. <strong>Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor.</strong> Hum. Molec. Genet. 12: 1497-1506, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812978</a>] [<a href="https://doi.org/10.1093/hmg/ddg161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812978">Mandrusiak et al. (2003)</a> hypothesized that crosslinked AR cannot be degraded by the proteasome and may obstruct the proteasome pore, preventing normal function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12812978" 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="#180" class="mim-tip-reference" title="Wang, Q., Carroll, J. S., Brown, M. <strong>Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking.</strong> Molec. Cell 19: 631-642, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16137620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16137620</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.07.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16137620">Wang et al. (2005)</a> found that AR regulation of PSA (KLK3; <a href="/entry/176820">176820</a>) in LNCaP cells involved both a promoter-proximal sequence and an enhancer about 4 kb upstream. Recruitment of AR and essential coactivators at both sites created a chromosomal loop that allowed RNA polymerase II to track from the enhancer to the promoter. Phosphorylation of the RNA pol II C-terminal domain was required for RNA pol II tracking but not chromosomal looping. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16137620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Chiu, C.-M., Yeh, S.-H., Chen, P.-J., Kuo, T.-J., Chang, C.-J., Chen, P.-J., Yang, W.-J., Chen, D.-S. <strong>Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level.</strong> Proc. Nat. Acad. Sci. 104: 2571-2578, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17259306[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.0609498104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259306">Chiu et al. (2007)</a> examined the roles of AR and the hepatitis B virus nonstructural protein HBx in hepatocellular carcinoma (<a href="/entry/114550">114550</a>), a disease that predominantly affects males. HBx increased the anchorage-independent colony formation potency of AR in a nontransformed mouse hepatocyte cell line. AR-mediated transcriptional activity was enhanced by HBx in an androgen concentration-dependent manner. Mutation analysis showed that HBx-enhanced AR gene transcriptional activity required intact HBx and the hinge region of AR. Immunoprecipitation and cell fractionation analyses revealed that HBx-AR interactions occurred mainly in the cytosol. HBx-enhanced AR activation involved SRC (<a href="/entry/190090">190090</a>) activity. <a href="#29" class="mim-tip-reference" title="Chiu, C.-M., Yeh, S.-H., Chen, P.-J., Kuo, T.-J., Chang, C.-J., Chen, P.-J., Yang, W.-J., Chen, D.-S. <strong>Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level.</strong> Proc. Nat. Acad. Sci. 104: 2571-2578, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17259306[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.0609498104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259306">Chiu et al. (2007)</a> concluded that HBx is a noncellular positive coregulator of AR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using protein pull-down and coimmunoprecipitation analyses, <a href="#179" class="mim-tip-reference" title="Wang, H., Jiang, M., Cui, H., Chen, M., Buttyan, R., Hayward, S. W., Hai, T., Wang, Z., Yan, C. <strong>The stress response mediator ATF3 represses androgen signaling by binding the androgen receptor.</strong> Molec. Cell. Biol. 32: 3190-3202, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22665497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22665497</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22665497[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.00159-12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22665497">Wang et al. (2012)</a> found that activating transcription factor-3 (ATF3; <a href="/entry/603148">603148</a>) interacted with AR. Mutation analysis revealed that the bZIP domain of ATF3 interacted with the DNA-binding and ligand-binding domains of AR. Binding of ATF3 inhibited interaction of AR with AREs in DNA and inhibited intramolecular interactions between the N- and C-terminal regions of AR. ATF3 did not interfere with binding between AR and androgen ligand, nor did it inhibit ligand-dependent nuclear translocation of AR. Expression of ATF3 repressed AR-mediated transactivation of an ARE reporter in a dose-dependent manner. Repression was independent of ATF3 transcriptional activity, but it required binding of ATF3 to AR, which blocked binding of AR to target promoters/enhancers. Knockdown of ATF3 via short hairpin RNA in human prostate cancer cell lines increased expression of AR-dependent genes, and knockout of Atf3 in mice promoted proliferation of prostate epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22665497" 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="#193" class="mim-tip-reference" title="Yang, L., Lin, C., Jin, C., Yang, J. C., Tanasa, B., Li, W., Merkurjev, D., Ohgi, K. A., Meng, D., Zhang, J., Evans, C. P., Rosenfeld, M. G. <strong>lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.</strong> Nature 500: 598-602, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23945587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23945587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23945587[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/nature12451" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23945587">Yang et al. (2013)</a> reported that 2 long noncoding RNAs (lncRNAs) highly overexpressed in aggressive prostate cancer, PRNCR1 (<a href="/entry/615452">615452</a>) and PCGEM1 (<a href="/entry/605443">605443</a>), bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated AR on enhancers and its association with DOT1L (<a href="/entry/607375">607375</a>) appear to be required for recruitment of the second lncRNA, PCGEM1, to the AR amino terminus, which is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus-2 (PYGO2; <a href="/entry/606903">606903</a>) PHD domain enhances selective looping of AR-bound enhancers to target gene promoters in these cells. In resistant prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumor xenograft growth in vivo. <a href="#193" class="mim-tip-reference" title="Yang, L., Lin, C., Jin, C., Yang, J. C., Tanasa, B., Li, W., Merkurjev, D., Ohgi, K. A., Meng, D., Zhang, J., Evans, C. P., Rosenfeld, M. G. <strong>lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.</strong> Nature 500: 598-602, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23945587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23945587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23945587[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/nature12451" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23945587">Yang et al. (2013)</a> concluded that these overexpressed lncRNAs can potentially serve as a required component of castration resistance in prostatic tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23945587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Blessing, A. M., Ganesan, S., Rajapakshe, K., Sung, Y. Y., Bollu, L. R., Shi, Y., Cheung, E., Coarfa, C., Chang, J. T., McDonnell, D. P., Frigo, D. E. <strong>Identification of a novel coregulator, SH3YL1, that interacts with the androgen receptor N-terminus.</strong> Molec. Endocr. 29: 1426-1439, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26305679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26305679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26305679[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/me.2015-1079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26305679">Blessing et al. (2015)</a> found that disruption of the pro-rich region within the N terminus of human AR reduced androgen-dependent proliferation and migration of human prostate cancer cells. Phage display analysis showed that SH3YL1 (<a href="/entry/617314">617314</a>) interacted with the AR pro-rich domain. Knockdown of SH3YL1 attenuated androgen-mediated cell growth and migration. RNA expression analysis revealed that SH3YL1 was required for induction of a subset of AR-modulated genes. UBN1 (<a href="/entry/609771">609771</a>), a key member of the histone H3.3 (see <a href="/entry/601128">601128</a>) chaperone complex, was a transcriptional target of the SH3YL1/AR complex, correlated with aggressive prostate cancer in patients, and was necessary for maximal androgen-mediated proliferation and migration of prostate cancer cells. <a href="#11" class="mim-tip-reference" title="Blessing, A. M., Ganesan, S., Rajapakshe, K., Sung, Y. Y., Bollu, L. R., Shi, Y., Cheung, E., Coarfa, C., Chang, J. T., McDonnell, D. P., Frigo, D. E. <strong>Identification of a novel coregulator, SH3YL1, that interacts with the androgen receptor N-terminus.</strong> Molec. Endocr. 29: 1426-1439, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26305679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26305679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26305679[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/me.2015-1079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26305679">Blessing et al. (2015)</a> concluded that the pro-rich N-terminal activation domain of AR, its SH3YL1 coregulator, and downstream transcriptional targets are involved in regulating processes important in prostate cancer pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26305679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By coimmunoprecipitation analysis, <a href="#165" class="mim-tip-reference" title="Sun, S., Zhong, X., Wang, C., Sun, H., Wang, S., Zhou, T., Zou, R., Lin, L., Sun, N., Sun, G., Wu, Y., Wang, B., Song, X., Cao, L., Zhao, Y. <strong>BAP18 coactivates androgen receptor action and promotes prostate cancer progression.</strong> Nucleic Acids Res. 44: 8112-8128, 2016. Note: Erratum: Nucleic Acids Res. 50: 597-598, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27226492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27226492</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27226492[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/10.1093/nar/gkw472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27226492">Sun et al. (2016)</a> showed that BAP18 (C17ORF49; <a href="/entry/617215">617215</a>) interacted with AR in transfected HEK293 and in 22Rv1 prostate carcinoma cells. BAP18 enhanced AR activation of a reporter gene in an androgen-dependent manner. BAP18 facilitated recruitment of AR and the MLL1 (KMT2A; <a href="/entry/159555">159555</a>) methyltransferase subcomplex to AREs in AR target genes, subsequently increasing histone H3 (see <a href="/entry/602810">602810</a>) lys4 trimethylation and H4 (see <a href="/entry/602822">602822</a>) lys16 acetylation. <a href="#165" class="mim-tip-reference" title="Sun, S., Zhong, X., Wang, C., Sun, H., Wang, S., Zhou, T., Zou, R., Lin, L., Sun, N., Sun, G., Wu, Y., Wang, B., Song, X., Cao, L., Zhao, Y. <strong>BAP18 coactivates androgen receptor action and promotes prostate cancer progression.</strong> Nucleic Acids Res. 44: 8112-8128, 2016. Note: Erratum: Nucleic Acids Res. 50: 597-598, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27226492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27226492</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27226492[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/10.1093/nar/gkw472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27226492">Sun et al. (2016)</a> concluded that BAP18 is an epigenetic modifier that regulates AR-induced transactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27226492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transcriptomic analysis, <a href="#197" class="mim-tip-reference" title="Zhang, Y., Pitchiaya, S., Cieslik, M., Niknafs, Y. S., Tien, J. C.-Y., Hosono, Y., Iyer, M. K., Yazdani, S., Subramaniam, S., Shukla, S. K., Jiang, X., Wang, L., and 25 others. <strong>Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ALRNC1 in prostate cancer progression.</strong> Nature Genet. 50: 814-824, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29808028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29808028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29808028[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/s41588-018-0120-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29808028">Zhang et al. (2018)</a> identified ARLNC1 (<a href="/entry/618053">618053</a>) as a prostate lineage-specific lncRNA directly regulated by AR via an AR-binding site in the promoter region of ARLNC1. Further analysis analysis identified FOXA1 (<a href="/entry/602294">602294</a>) as an additional regulator of ARLNC1, with expression of AR and FOXA1 overlapping nearly exclusively in prostate tissue. ARLNC1 knockdown in human prostate cancer cells significantly decreased AR expression, suppressed genes positively regulated by AR, and upregulated genes negatively regulated by AR, suggesting a positive-feedback loop between ARLNC1 and AR. ARLNC1 and AR transcripts colocalized, and the authors found that nucleotides 700 to 1300 of ARLNC1 were critical for binding to the 3-prime UTR of the AR transcript. Tracking of the subcellular localization of AR transcripts in an ARLNC1-depleted prostate cancer cell line showed that ARLNC1 regulated the cytoplasmic levels of AR transcripts. Knockdown of ARLNC1 inhibited proliferation and promoted apoptosis in AR-positive prostate cancer cells, and tissue-specific knockdown of Arlnc1 in mice significantly decreased tumor growth compared with controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29808028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Studies on the AR Protein with an Expanded Polyglutamine Repeat</em></strong></p><p>
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<a href="#30" class="mim-tip-reference" title="Choong, C. S., Kemppainen, J. A., Zhou, Z.-X., Wilson, E. M. <strong>Reduced androgen receptor gene expression with first exon CAG repeat expansion.</strong> Molec. Endocr. 10: 1527-1535, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8961263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8961263</a>] [<a href="https://doi.org/10.1210/mend.10.12.8961263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8961263">Choong et al. (1996)</a> found an inverse relationship between AR CAG repeat length and AR mRNA and protein levels in an in vitro model using transient transfection of human AR expression vectors. Trinucleotide repeat lengths of 43 and 65 associated with X-linked spinal and bulbar muscular atrophy decreased AR mRNA and protein levels, but did not alter equilibrium binding affinity for a synthetic androgen or the AR transcriptional activity. These findings indicated that glutamate expansions of up to 66 residues in the first AR exon did not alter AR functional activity but did reduce AR mRNA and protein expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8961263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Butler, R., Leigh, P. N., McPhaul, M. J., Gallo, J.-M. <strong>Truncated forms of the androgen receptor are associated with polyglutamine expansion in X-linked spinal and bulbar muscular atrophy.</strong> Hum. Molec. Genet. 7: 121-127, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9384612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9384612</a>] [<a href="https://doi.org/10.1093/hmg/7.1.121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9384612">Butler et al. (1998)</a> found that transfection of an SBMA mutant androgen receptor (52 CAG repeats) into mouse neuroblastoma cells enhanced the production of C-terminally truncated fragments of the androgen receptor protein. A 74-kD fragment was particularly prominent in cells expressing the SBMA androgen receptor. From its size, it could be deduced that the 74-kD fragment lacked the hormone-binding domain but retained the DNA-binding domain. The 74-kD fragment may, therefore, be toxic to motor neurons by initiating the transcription of specific genes in the absence of hormonal control. Immunofluorescence microscopy on transfected neuroblastoma cells showed that the wildtype androgen receptor translocated to the nucleus after hormone activation, whereas the SBMA androgen receptor was mainly localized in the cytoplasm in the form of dense aggregates with very little androgen receptor protein in the nucleus. The findings could explain the reduction in transcriptional activity of the SBMA mutant as compared with wildtype androgen receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9384612" 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="#81" class="mim-tip-reference" title="Kobayashi, Y., Miwa, S., Merry, D. E., Kume, A., Mei, L., Doyu, M., Sobue, G. <strong>Caspase-3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner.</strong> Biochem. Biophys. Res. Commun. 252: 145-150, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9813160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9813160</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9624" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9813160">Kobayashi et al. (1998)</a> showed that in vitro translated full-length AR proteins containing different sized polyglutamine repeats (24, 65, and 97 repeats, respectively) were specifically cleaved by recombinant caspase-3 (CASP3; <a href="/entry/600636">600636</a>), liberating a polyglutamine-containing fragment, and that the susceptibility to cleavage was polyglutamine repeat length-dependent. These findings suggested that the AR protein is one of the 'death substrates' cleaved by caspase-3 and that caspase-3 may be involved in the pathogenesis of SBMA. <a href="#120" class="mim-tip-reference" title="Merry, D. E., Kobayashi, Y., Bailey, C. K., Taye, A. A., Fischbeck, K. H. <strong>Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy.</strong> Hum. Molec. Genet. 7: 693-701, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499423</a>] [<a href="https://doi.org/10.1093/hmg/7.4.693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499423">Merry et al. (1998)</a> found that transfection of a truncated AR protein with expanded CAG repeats into COS-7 cells resulted in increased cell death. Western blot analysis showed that the expanded protein underwent proteolytic cleavage within the polyglutamine tract and formed intracellular aggregates in a repeat length-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9813160+9499423" 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="#161" class="mim-tip-reference" title="Simeoni, S., Mancini, M. A., Stenoien, D. L., Marcelli, M., Weigel, N. L., Zanisi, M., Martini, L., Poletti, A. <strong>Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract.</strong> Hum. Molec. Genet. 9: 133-144, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587588</a>] [<a href="https://doi.org/10.1093/hmg/9.1.133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587588">Simeoni et al. (2000)</a> produced a model to study the effects of potentially 'neurotoxic' polyglutamine aggregates in SBMA using immortalized motoneuronal cells transfected with AR containing polyglutamine repeats of different sizes (zero, 23, or 46 repeats). Using chimeras of the modified AR protein and the green fluorescent protein (GFP), they showed that aggregate formation occurs when the polyglutamine tract is elongated and AR is activated by androgens. In the cells coexpressing AR with the polyglutamine of pathologic length (46 repeats) and the GFP, <a href="#161" class="mim-tip-reference" title="Simeoni, S., Mancini, M. A., Stenoien, D. L., Marcelli, M., Weigel, N. L., Zanisi, M., Martini, L., Poletti, A. <strong>Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract.</strong> Hum. Molec. Genet. 9: 133-144, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587588</a>] [<a href="https://doi.org/10.1093/hmg/9.1.133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587588">Simeoni et al. (2000)</a> noted the presence of several dystrophic neurites. Cell viability analyses showed a reduced growth/survival rate in the cells expressing the polyglutamine of pathologic length, whereas testosterone treatment partially counteracted both cell death and the formation of dystrophic neurites. These observations indicated the lack of correlation between aggregate formation and cell survival, and suggested that neuronal degeneration in SBMA may be secondary to axonal/dendritic insults. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587588" 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="#110" class="mim-tip-reference" title="McCampbell, A., Taylor, J. P., Taye, A. A., Robitschek, J., Li, M., Walcott, J., Merry, D., Chai, Y., Paulson, H., Sobue, G., Fischbeck, K. H. <strong>CREB-binding protein sequestration by expanded polyglutamine.</strong> Hum. Molec. Genet. 9: 2197-2202, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958659</a>] [<a href="https://doi.org/10.1093/hmg/9.14.2197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10958659">McCampbell et al. (2000)</a> demonstrated that CREB-binding protein (CREBBP; <a href="/entry/600140">600140</a>), a transcriptional coactivator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice, and tissue from patients with SBMA. Soluble levels of CREB-binding protein were reduced in cells expressing expanded polyglutamine despite increased levels of CREBBP mRNA. Overexpression of CREBBP rescued cells from polyglutamine-mediated toxicity in neuronal cell culture. The authors proposed a CREBBP-sequestration model of polyglutamine expansion disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10958659" 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="#183" class="mim-tip-reference" title="Welch, W. J., Diamond, M. I. <strong>Glucocorticoid modulation of androgen receptor nuclear aggregation and cellular toxicity is associated with distinct forms of soluble expanded polyglutamine protein.</strong> Hum. Molec. Genet. 10: 3063-3074, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751688</a>] [<a href="https://doi.org/10.1093/hmg/10.26.3063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11751688">Welch and Diamond (2001)</a> used the wildtype glucocorticoid receptor (GR; <a href="/entry/138040">138040</a>) and a mutated form of the GR (GR-delta-109-317) to study expanded polyglutamine AR protein in different cell contexts. The authors found that wildtype GR promoted soluble forms of the AR protein and prevented nuclear aggregation in NIH 3T3 cells and cultured neurons. In contrast, GR-delta-108-317 decreased polyglutamine protein solubility, and caused formation of nuclear aggregates in nonneuronal cells. Nuclear aggregates recruited the heat-shock protein Hsp70 (see <a href="/entry/140550">140550</a>) more rapidly than cytoplasmic aggregates, and were associated with decreased cell viability. Limited proteolysis and chemical crosslinking suggested that unique soluble forms of the expanded AR protein may underlie these distinct biologic activities. The authors hypothesized that unique protein associations or conformations of expanded polyglutamine proteins may determine subsequent cellular effects such as nuclear localization and cellular toxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11751688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bailey, C. K., Andriola, I. F. M., Kampinga, H. H., Merry, D. E. <strong>Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.</strong> Hum. Molec. Genet. 11: 515-523, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875046</a>] [<a href="https://doi.org/10.1093/hmg/11.5.515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11875046">Bailey et al. (2002)</a> developed a cell culture system which afforded quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. The authors demonstrated that Hsp70 and its co-chaperone Hsp40 (see <a href="/entry/604572">604572</a>) not only increased expanded repeat AR solubility, but enhanced the degradation of expanded repeat AR through the proteasome. Furthermore, these chaperones significantly decreased the half-life of an expanded repeat AR, suggesting that upregulation of molecular chaperones may be a potential therapeutic target for polyglutamine diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875046" 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>RNA interference is a mechanism that appears to control unwanted gene expression in a wide range of species. To test if RNA interference can be used to specifically downregulate a human disease-related transcript, <a href="#23" class="mim-tip-reference" title="Caplen, N. J., Taylor, J. P., Statham, V. S., Tanaka, F., Fire, A., Morgan, R. A. <strong>Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference.</strong> Hum. Molec. Genet. 11: 175-184, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809726</a>] [<a href="https://doi.org/10.1093/hmg/11.2.175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809726">Caplen et al. (2002)</a> devised Drosophila and human tissue culture models of SBMA. A variety of different double-stranded RNAs (dsRNAs) were assessed for the ability to inhibit expression of transcripts that included a truncated human androgen receptor gene containing different CAG repeat lengths (16 to 112 repeats). In mammalian cells, sequence-specific small dsRNAs of 22 nucleotides rescued the toxicity and caspase-3 activation induced by plasmids expressing a transcript encoding an expanded polyglutamine tract. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11809726" 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="#94" class="mim-tip-reference" title="Lieberman, A. P., Harmison, G., Strand, A. D., Olson, J. M., Fischbeck, K. H. <strong>Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor.</strong> Hum. Molec. Genet. 11: 1967-1976, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12165558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12165558</a>] [<a href="https://doi.org/10.1093/hmg/11.17.1967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12165558">Lieberman et al. (2002)</a> showed that the mouse MN-1 cultured cell line expressing the wildtype androgen receptor (with 24 CAG repeats) responded to ligand by showing trophic effects including prolonged survival in low serum, whereas cells expressing the mutant receptor (with 65 CAG repeats) did not show a robust trophic response. This partial loss of function correlated with decreased levels of the mutant protein due to its preferential degradation by the ubiquitin-proteasome pathway. Expression analysis using oligonucleotide arrays confirmed that the mutant receptor underwent a partial loss of function, and failed to regulate a subset of genes whose expression is normally affected by ligand activation of the wildtype receptor. The authors concluded that polyglutamine expansion alters androgen receptor function by promoting its degradation and by modifying its activity as a transcription factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12165558" 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>Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes.' <a href="#170" class="mim-tip-reference" title="Taylor, J. P., Tanaka, F., Robitschek, J., Sandoval, C. M., Taye, A., Markovic-Plese, S., Fischbeck, K. H. <strong>Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein.</strong> Hum. Molec. Genet. 12: 749-757, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12651870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12651870</a>] [<a href="https://doi.org/10.1093/hmg/ddg074" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12651870">Taylor et al. (2003)</a> showed that mutant GFP-tagged androgen receptor (AR-112Q) formed insoluble aggregates and was toxic to cultured transfected cells. Using molecular and pharmacologic interventions to disrupt aggresome formation, the authors found that aggresome-forming proteins had an accelerated rate of turnover which was slowed by inhibition of aggresome formation, became membrane-bound, and associated with lysosomal structures. <a href="#170" class="mim-tip-reference" title="Taylor, J. P., Tanaka, F., Robitschek, J., Sandoval, C. M., Taye, A., Markovic-Plese, S., Fischbeck, K. H. <strong>Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein.</strong> Hum. Molec. Genet. 12: 749-757, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12651870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12651870</a>] [<a href="https://doi.org/10.1093/hmg/ddg074" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12651870">Taylor et al. (2003)</a> suggested that aggresomes may be cytoprotective and serve as cytoplasmic recruitment centers to facilitate degradation of toxic proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12651870" 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 vitro, <a href="#167" class="mim-tip-reference" title="Szebenyi, G., Morfini, G. A., Babcock, A., Gould, M., Selkoe, K., Stenoien, D. L., Young, M., Faber, P. W., MacDonald, M. E., McPhaul, M. J., Brady, S. T. <strong>Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport.</strong> Neuron 40: 41-52, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14527432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14527432</a>] [<a href="https://doi.org/10.1016/s0896-6273(03)00569-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14527432">Szebenyi et al. (2003)</a> showed that androgen receptor and huntingtin (<a href="/entry/613004">613004</a>) polypeptides containing pathogenic polyglutamine (polyQ) repeats directly inhibited both fast axonal transport and elongation of neuritic processes. The effects were greater with truncated polypeptides and occurred without detectable morphologic aggregates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14527432" 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="#88" class="mim-tip-reference" title="LaFevre-Bernt, M. A., Ellerby, L. M. <strong>Kennedy's disease: phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its clevage (sic) by caspase-3 and enhances cell death.</strong> J. Biol. Chem. 278: 34918-34924, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12824190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12824190</a>] [<a href="https://doi.org/10.1074/jbc.M302841200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12824190">LaFevre-Bernt and Ellerby (2003)</a> found that expression of an expanded AR protein with 112 CAG repeats in human kidney cells activated 3 MAP kinase pathways, causing increased levels of phosphorylation of p44/42 (<a href="/entry/601795">601795</a>), p38 (<a href="/entry/600289">600289</a>), and SAPK/JNK (<a href="/entry/601158">601158</a>). Only inhibition of the p44/42 MAP kinase pathway reduced cell death, reduced the cleavage of expanded AR, and decreased phosphorylation of the expanded AR. <a href="#88" class="mim-tip-reference" title="LaFevre-Bernt, M. A., Ellerby, L. M. <strong>Kennedy's disease: phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its clevage (sic) by caspase-3 and enhances cell death.</strong> J. Biol. Chem. 278: 34918-34924, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12824190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12824190</a>] [<a href="https://doi.org/10.1074/jbc.M302841200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12824190">LaFevre-Bernt and Ellerby (2003)</a> postulated that phosphorylation at serine-514 of the AR protein is repeat length-dependent, and that phosphorylation enhances the ability of caspase-3 to cleave AR and generate toxic polyQ fragments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12824190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Buchanan, G., Yang, M., Cheong, A., Harris, J. M., Irvine, R. A., Lambert, P. F., Moore, N. L., Raynor, M., Neufing, P. J., Coetzee, G. A., Tilley, W. D. <strong>Structural and functional consequences of glutamine tract variation in the androgen receptor.</strong> Hum. Molec. Genet. 13: 1677-1692, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198988</a>] [<a href="https://doi.org/10.1093/hmg/ddh181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198988">Buchanan et al. (2004)</a> characterized a somatic AR gene mutation from a human prostate tumor that resulted in interruption of the polyQ tract by 2 nonconsecutive leucine residues (AR-polyQ2L). Compared with wildtype AR, AR-polyQ2L exhibited disrupted interdomain communication (N/C interaction) and a lower protein level but paradoxically had markedly increased transactivation activity. Molecular modeling and the response to cofactors indicated that the increased activity of AR-polyQ2L resulted from presentation of a more stable platform for the recruitment of accessory proteins than wildtype AR. Analysis of the relationship between polyQ tract length and AR function revealed a critical size (16 to 29 glutamines) for maintenance of N/C interaction. Since 91 to 99% of AR alleles in different racial/ethnic groups encode a polyQ tract in the range of 16 to 29 glutamines, <a href="#18" class="mim-tip-reference" title="Buchanan, G., Yang, M., Cheong, A., Harris, J. M., Irvine, R. A., Lambert, P. F., Moore, N. L., Raynor, M., Neufing, P. J., Coetzee, G. A., Tilley, W. D. <strong>Structural and functional consequences of glutamine tract variation in the androgen receptor.</strong> Hum. Molec. Genet. 13: 1677-1692, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198988</a>] [<a href="https://doi.org/10.1093/hmg/ddh181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198988">Buchanan et al. (2004)</a> suggested that N/C interaction may have been preserved as an essential component of androgen-induced AR signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15198988" 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="#150" class="mim-tip-reference" title="Ranganathan, S., Harmison, G. G., Meyertholen, K., Pennuto, M., Burnett, B. G., Fischbeck, K. H. <strong>Mitochondrial abnormalities in spinal and bulbar muscular atrophy.</strong> Hum. Molec. Genet. 18: 27-42, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824496</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824496[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/10.1093/hmg/ddn310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824496">Ranganathan et al. (2009)</a> found that constitutive and doxycycline-induced expression of mutant AR with 65 CAG repeats (AR-65Q) in MN-1 and PC12 cells, respectively, were associated with depolarization of the mitochondrial membrane. This was mitigated by cyclosporine A, which inhibits opening of the mitochondrial permeability transition pore. Expression of AR-65Q in the presence of ligand resulted in an elevated level of reactive oxygen species, which was blocked by treatment with the antioxidants coenzyme Q10 and idebenone. The 65Q-mutant AR protein in MN-1 cells also resulted in increased Bax (<a href="/entry/600040">600040</a>), caspase-9 (CASP9; <a href="/entry/602234">602234</a>), and caspase-3 (CASP3; <a href="/entry/600636">600636</a>). There was altered expression of peroxisome proliferator-activated receptor gamma coactivator-1A (PPARGC1A; <a href="/entry/604517">604517</a>) and SOD2 (<a href="/entry/147460">147460</a>) in affected tissues of SBMA knockin mice. Subcelluar fractionation and electron microscopy of MN-1 and PC12 cells showed that AR-65Q mutant associated with mitochondria. <a href="#150" class="mim-tip-reference" title="Ranganathan, S., Harmison, G. G., Meyertholen, K., Pennuto, M., Burnett, B. G., Fischbeck, K. H. <strong>Mitochondrial abnormalities in spinal and bulbar muscular atrophy.</strong> Hum. Molec. Genet. 18: 27-42, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824496</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824496[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/10.1093/hmg/ddn310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824496">Ranganathan et al. (2009)</a> concluded that there is mitochondrial dysfunction in SBMA cells and animal models, either through indirect effects on the transcription of nuclear-encoded mitochondrial genes or through direct effects of the mutant AR protein on mitochondria, or both. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824496" 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 somatic cell hybridization, <a href="#123" class="mim-tip-reference" title="Migeon, B. R., Brown, T. R., Axelman, J., Migeon, C. J. <strong>Studies of the locus for androgen receptor: localization on the human X and evidence for homology with the Tfm locus in the mouse.</strong> Proc. Nat. Acad. Sci. 78: 6339-6343, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6947233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6947233</a>] [<a href="https://doi.org/10.1073/pnas.78.10.6339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6947233">Migeon et al. (1981)</a> found that the androgen receptor locus is located between Xq13 and Xp11 and is proximal to the locus for PGK (<a href="/entry/311800">311800</a>). It may be located in the Xq11 region, judging by the findings in 1 rearrangement with a break there. Lack of complementation with cells from Tfm of the mouse indicated homology. Rearrangement must have occurred in evolution, however, because the Tfm locus is not near the centromere in the mouse. Findings consistent with localization of the human TFM locus to proximal Xq near the centromere were reported by <a href="#186" class="mim-tip-reference" title="Wieacker, P., Breckwoldt, M., Gal, A. <strong>Testicular feminization: diagnosis and search for closely linked restriction fragment length polymorphism.</strong> Dis. Markers 3: 213-218, 1985."None>Wieacker et al. (1985)</a> who found a carrier woman heterozygous for a RFLP of a probe called p8, localized between Xcen and Xq13; 4 affected children had inherited the same p8 allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6947233" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 families with testicular feminization and 1 family with Reifenstein syndrome, <a href="#187" class="mim-tip-reference" title="Wieacker, P., Griffin, J. E., Wienker, T., Lopez, J. M., Wilson, J. D., Breckwoldt, M. <strong>Linkage analysis with RFLPs in families with androgen resistance syndromes: evidence for close linkage between the androgen receptor locus and the DXS1 segment.</strong> Hum. Genet. 76: 248-252, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2885254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2885254</a>] [<a href="https://doi.org/10.1007/BF00283617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2885254">Wieacker et al. (1987)</a> found close linkage (indeed, no recombination) between the disease phenotype and DNA marker DXS1. Assuming that the 2 disorders are allelic, the summarized data led to a maximum lod score of 3.5 at theta = 0.0. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2885254" 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="#100" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sar, M., Tan, J., Higgs, H. N., Larson, R. E., French, F. S., Wilson, E. M. <strong>The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate.</strong> Molec. Endocr. 2: 1265-1275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3216866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3216866</a>] [<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3216866">Lubahn et al. (1988)</a> cloned human AR genomic DNA from a flow-sorted human X chromosome library by using a consensus nucleotide sequence from the DNA-binding domain of the family of nuclear receptors. They localized the gene to the region between the centromere and Xq13 by studying human-rodent hybrids in which the human X chromosome was fragmented. Using a cloned cDNA for AR, <a href="#15" class="mim-tip-reference" title="Brown, C. J., Goss, S. J., Lubahn, D. B., Joseph, D. R., Wilson, E. M., French, F. S., Willard, H. F. <strong>Androgen receptor locus on the human X chromosome: regional localization to Xq11-12 and description of a DNA polymorphism.</strong> Am. J. Hum. Genet. 44: 264-269, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2563196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2563196</a>]" pmid="2563196">Brown et al. (1989)</a> localized the AR gene to Xq11-q12 by analysis of somatic cell hybrid panels segregating portions of the X chromosome. They also found a RFLP that should be useful in linkage analysis of various forms of inherited androgen insensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2563196+3216866" 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 most extensively affected kindred known with complete androgen insensitivity (CAIS), one living in the Dominican Republic, <a href="#67" class="mim-tip-reference" title="Imperato-McGinley, J., Ip, N. Y., Gautier, T., Neuweiler, J., Gruenspan, H., Liao, S., Chang, C., Balazs, I. <strong>DNA linkage analysis and studies of the androgen receptor gene in a large kindred with complete androgen insensitivity.</strong> Am. J. Med. Genet. 36: 104-108, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2333898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2333898</a>] [<a href="https://doi.org/10.1002/ajmg.1320360121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2333898">Imperato-McGinley et al. (1990)</a> found linkage to DXS1 and PGK1, localizing the AR gene to an area between Xq11 and Xq13. Linkage between DXS1 and AR showed a peak lod score of 3.2 at theta = 0.06. No recombination was found between PGK1 and AR; peak lod score was 2.9 at theta = 0.0. Although both AR and PGK1 are distal to DXS1, it was not possible to determine the sequence of the two. Using 3 cDNA probes spanning various parts of the AR gene, they could demonstrate no abnormality in restriction fragment patterns, suggesting that the gene defect is not a deletion but rather a point mutation or a small insertion/deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2333898" 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="#141" class="mim-tip-reference" title="Patterson, M. N., Hughes, I. A., Gottlieb, B., Pinsky, L. <strong>The androgen receptor gene mutations database.</strong> Nucleic Acids Res. 22: 3560-3562, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7937057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7937057</a>]" pmid="7937057">Patterson et al. (1994)</a> described a database of AR gene mutations, which included 114 unique mutations. <a href="#50" class="mim-tip-reference" title="Gottlieb, B., Trifiro, M., Lumbroso, R., Vasiliou, D. M., Pinsky, L. <strong>The androgen receptor gene mutations database.</strong> Nucleic Acids Res. 24: 151-154, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8594566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8594566</a>] [<a href="https://doi.org/10.1093/nar/24.1.151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8594566">Gottlieb et al. (1996)</a> described the latest version of their AR mutation database which contained 212 entries representing 239 patients with androgen insensitivity syndrome (<a href="/entry/300068">300068</a>) or prostate cancer (<a href="/entry/301120">301120</a>) bearing 155 different AR mutations. <a href="#49" class="mim-tip-reference" title="Gottlieb, B., Trifiro, M., Lumbroso, R., Pinsky, L. <strong>The androgen receptor gene mutations database.</strong> Nucleic Acids Res. 25: 158-162, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9016528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9016528</a>] [<a href="https://doi.org/10.1093/nar/25.1.158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9016528">Gottlieb et al. (1997)</a> stated that the number of reported mutations in their database had risen from 212 to 272. To complement the database, they had constructed mutation maps for AIS phenotypes and for prostate cancer, classified the number and variety of mutation types, and tabulated information on the multiplicity of the CpG-site mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9016528+7937057+8594566" 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 an update on the AR gene mutation database, <a href="#48" class="mim-tip-reference" title="Gottlieb, B., Beitel, L. K., Wu, J. H., Trifiro, M. <strong>The androgen receptor gene mutations database (ARDB): 2004 update.</strong> Hum. Mutat. 23: 527-533, 2004. Note: Erratum: Hum. Mutat. 24: 102 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15146455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15146455</a>] [<a href="https://doi.org/10.1002/humu.20044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15146455">Gottlieb et al. (2004)</a> stated that the reported mutations had risen from 374 to 605, and the number of AR-interacting proteins described had increased from 23 to 70, over the previous 3 years. In addition, silent mutations had been reported in both androgen insensitivity syndrome and prostate cancer cases. The database also incorporated information on spinobulbar muscular atrophy (SBMA; <a href="/entry/313200">313200</a>), which is caused by a CAG repeat in exon 1 of the AR gene, as well as CAG repeat length variations associated with risk for breast, endometrial, colorectal, and prostate cancer, as well as for male infertility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15146455" 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="#128" class="mim-tip-reference" title="Mooney, S. D., Klein, T. E., Altman, R. B., Trifiro, M. A., Gottlieb, B. <strong>A functional analysis of disease-associated mutations in the androgen receptor gene.</strong> Nucleic Acids Res. 31: e42, 2003. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12682377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12682377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12682377[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/10.1093/nar/gng042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12682377">Mooney et al. (2003)</a> presented a method for distinguishing disease-causing mutations in the AR gene from mutations that are associated with disease but have no causal role. They used a measure of nucleotide conservation among similar genes as well as AR mutations previously identified as disease-causing in various forms of AIS and prostate cancer. The degree of conservation of disease-causing mutations correlated with the severity of the AIS phenotype, and experimentally proven prostate cancer-linked mutations were found to occur in highly conserved regions of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12682377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate whether androgen sensitivity, indicated by the length of the CAG repeat in the AR gene, has a role in the pathogenesis of premature adrenarche, <a href="#89" class="mim-tip-reference" title="Lappalainen, S., Utriainen, P., Kuulasmaa, T., Voutilainen, R., Jaaskelainen, J. <strong>Androgen receptor gene CAG repeat polymorphism and X-chromosome inactivation in children with premature adrenarche.</strong> J. Clin. Endocr. Metab. 93: 1304-1309, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252782</a>] [<a href="https://doi.org/10.1210/jc.2007-2707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252782">Lappalainen et al. (2008)</a> performed a cross-sectional association study among 73 Finnish Caucasian children with premature adrenarche (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). The methylation-weighted CAGn (mwCAGn) was determined via CAGn length and X-chromosome inactivation analysis, and clinical phenotype recorded. Subjects with premature adrenarche had significantly shorter mwCAGn than controls (mean difference (95% confidence interval); 0.76 (0.14-1.38); P = 0.017). AR gene mwCAGn did not correlate with androgen or SHBG (<a href="/entry/182205">182205</a>) levels in either group. The mean of mwCAGn was significantly shorter in children with premature adrenarche with lower BMI compared with those with higher BMI and in those with premature adrenarche and lower BMI compared with healthy children with same BMI. <a href="#89" class="mim-tip-reference" title="Lappalainen, S., Utriainen, P., Kuulasmaa, T., Voutilainen, R., Jaaskelainen, J. <strong>Androgen receptor gene CAG repeat polymorphism and X-chromosome inactivation in children with premature adrenarche.</strong> J. Clin. Endocr. Metab. 93: 1304-1309, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252782</a>] [<a href="https://doi.org/10.1210/jc.2007-2707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252782">Lappalainen et al. (2008)</a> concluded that AR gene CAGn polymorphism may have a significant role in the pathogenesis of premature adrenarche, especially in lean children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hypospadias and Cryptorchidism</em></strong></p><p>
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Because polymorphic CAG and GGN segments regulate AR function, <a href="#3" class="mim-tip-reference" title="Aschim, E. L., Nordenskjold, A., Giwercman, A., Lundin, K. B., Ruhayel, Y., Haugen, T. B., Grotmol, T., Giwercman, Y. L. <strong>Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene.</strong> J. Clin. Endocr. Metab. 89: 5105-5109, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472213</a>] [<a href="https://doi.org/10.1210/jc.2004-0293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15472213">Aschim et al. (2004)</a> investigated if there was an association between these polymorphisms and hypospadias (<a href="/entry/300633">300633</a>) and cryptorchidism (see <a href="/entry/219050">219050</a>). Genotyping was performed by direct sequencing of DNA from patients diagnosed with hypospadias and cryptorchidism and controls. The subjects with hypospadias were divided into subgroups of glanular, penile, and penoscrotal hypospadias. Median GGN lengths were significantly higher (24 vs 23) among subjects with cryptorchidism compared with controls (P = 0.001) and those with penile hypospadias, compared with either controls (P = 0.003) or glanular and penoscrotal hypospadias combined (P = 0.018). The frequency of cases with GGN 24 or more vs GGN = 23 differed significantly among those with cryptorchidism (65/35%) compared with controls (31/54%) (P = 0.012), and among subjects with penile hypospadias (69/31%) compared with either controls (P = 0.035) or glanular or penoscrotal hypospadias combined (32/55%) (P = 0.056). There were no significant differences in CAG lengths between the cases and controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15472213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Androgen Insensitivity Syndrome</em></strong></p><p>
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<a href="#117" class="mim-tip-reference" title="McPhaul, M. J., Marcelli, M., Zoppi, S., Wilson, C. M., Griffin, J. E., Wilson, J. D. <strong>Mutations in the ligand-binding domain of the androgen receptor gene cluster in two regions of the gene.</strong> J. Clin. Invest. 90: 2097-2101, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1430233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1430233</a>] [<a href="https://doi.org/10.1172/JCI116093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1430233">McPhaul et al. (1992)</a> analyzed the nucleotide sequence of the AR gene from 22 unrelated subjects with substitution mutations of the hormone-binding domain. Eleven had the phenotype of complete testicular feminization, 4 had incomplete testicular feminization, and 7 had Reifenstein syndrome. The functional defect included absence of ligand binding in 10 subjects and qualitative or quantitative defects in binding in 10 and 2 subjects, respectively. They observed that of 19 of the 21 substitution mutations (90%) clustered in 2 regions that account for approximately 35% of the hormone-binding domain, namely, between amino acids 726 and 772 and between amino acids 826 and 864. The fact that one of these regions is homologous to a region of the human thyroid hormone receptor that is a known cluster site for mutations that cause thyroid hormone resistance implies that the localization of mutations in the AR gene is not coincidence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1430233" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family in which 3 members had the complete form of the androgen insensitivity syndrome, <a href="#149" class="mim-tip-reference" title="Quigley, C. A., Friedman, K. J., Johnson, A., Lafreniere, R. G., Silverman, L. M., Lubahn, D. B., Brown, T. R., Wilson, E. M., Willard, H. F., French, F. S. <strong>Complete deletion of the androgen receptor gene: definition of the null phenotype of the androgen insensitivity syndrome and determination of carrier status.</strong> J. Clin. Endocr. Metab. 74: 927-933, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1347772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1347772</a>] [<a href="https://doi.org/10.1210/jcem.74.4.1347772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1347772">Quigley et al. (1992)</a> found complete deletion of the AR gene in affected persons and showed that the mutation had originated in the germline of the maternal great-grandfather of the index patient. <a href="#149" class="mim-tip-reference" title="Quigley, C. A., Friedman, K. J., Johnson, A., Lafreniere, R. G., Silverman, L. M., Lubahn, D. B., Brown, T. R., Wilson, E. M., Willard, H. F., French, F. S. <strong>Complete deletion of the androgen receptor gene: definition of the null phenotype of the androgen insensitivity syndrome and determination of carrier status.</strong> J. Clin. Endocr. Metab. 74: 927-933, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1347772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1347772</a>] [<a href="https://doi.org/10.1210/jcem.74.4.1347772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1347772">Quigley et al. (1992)</a> stated that mutation analysis had been performed in at least 60 unrelated persons and that in about half, a distinct single basepair mutation had been identified; the mutation produced an alteration in amino acid sequence, introducing a premature termination codon, or, in one case, resulting in aberrant mRNA splicing (<a href="#151" class="mim-tip-reference" title="Ris-Stalpers, C., Kuiper, G. G. J. M., Faber, P. W., Schweikert, H. U., van Rooij, H. C. J., Zegers, N. D., Hodgins, M. B., Degenhart, H. J., Trapman, J., Brinkmann, A. O. <strong>Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity.</strong> Proc. Nat. Acad. Sci. 87: 7866-7870, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236003</a>] [<a href="https://doi.org/10.1073/pnas.87.20.7866" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236003">Ris-Stalpers et al., 1990</a>). Complete or partial gene deletions appear to be a rare molecular cause of the androgen insensitivity syndrome. <a href="#149" class="mim-tip-reference" title="Quigley, C. A., Friedman, K. J., Johnson, A., Lafreniere, R. G., Silverman, L. M., Lubahn, D. B., Brown, T. R., Wilson, E. M., Willard, H. F., French, F. S. <strong>Complete deletion of the androgen receptor gene: definition of the null phenotype of the androgen insensitivity syndrome and determination of carrier status.</strong> J. Clin. Endocr. Metab. 74: 927-933, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1347772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1347772</a>] [<a href="https://doi.org/10.1210/jcem.74.4.1347772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1347772">Quigley et al. (1992)</a> pointed out that the affected individuals in their family had sparse, fine, blond vellus hair over the labia majora and emphasized that this should not be referred to as pubic hair. The pubertal transformation of vellus hair into the longer, coarser, darker terminal hair characteristic of adult pubic and axillary regions is androgen dependent. They suggested that the term 'sparse pubic hair' be used only in reference to hair of the same quality as normal androgen-dependent terminal hair but of diminished quantity, and that the term complete androgen insensitivity syndrome be reserved for those patients with complete absence of true sexual hair. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2236003+1347772" 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="#116" class="mim-tip-reference" title="McPhaul, M. J., Marcelli, M., Zoppi, S., Griffin, J. E., Wilson, J. D. <strong>Genetic basis of endocrine disease 4: the spectrum of mutations in the androgen receptor gene that causes androgen resistance.</strong> J. Clin. Endocr. Metab. 76: 17-23, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8421085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8421085</a>] [<a href="https://doi.org/10.1210/jcem.76.1.8421085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8421085">McPhaul et al. (1993)</a> summarized the spectrum of AR gene mutations in 31 unrelated subjects with various forms of androgen resistance syndrome. Most of the mutations were due to nucleotide changes that caused premature termination codons or single amino acid substitutions within the open reading frame, and most of these substitutions were localized in 3 regions of the androgen receptor: the DNA-binding domain and 2 segments of the androgen-binding domain. Less frequently, partial or complete gene deletions had been identified. <a href="#164" class="mim-tip-reference" title="Sultan, C., Lumbroso, S., Poujol, N., Belon, C., Boudon, C., Lobaccaro, J.-M. <strong>Mutations of androgen receptor gene in androgen insensitivity syndromes.</strong> J. Steroid Biochem. Molec. Biol. 46: 519-530, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8240973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8240973</a>] [<a href="https://doi.org/10.1016/0960-0760(93)90178-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8240973">Sultan et al. (1993)</a> tabulated 45 different mutations in the AR gene observed in patients with the complete androgen insensitivity syndrome, and 27 mutations found in patients with partial androgen insensitivity syndrome (PAIS). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8421085+8240973" 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 5 subjects in 4 families with androgen insensitivity, <a href="#129" class="mim-tip-reference" title="Murono, K., Mendonca, B. B., Arnhold, I. J. P., Rigon, A. C. M. M., Migeon, C. J., Brown, T. R. <strong>Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid-binding domain.</strong> Hum. Mutat. 6: 152-162, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581399</a>] [<a href="https://doi.org/10.1002/humu.1380060208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581399">Murono et al. (1995)</a> identified mutations in the steroid-binding domain of the androgen receptor. Four of the subjects, including 2 sibs, had CAIS; 1 subject with ambiguous genitalia had a missense mutation (<a href="#0008">313700.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581399" 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="#152" class="mim-tip-reference" title="Rodien, P., Mebarki, F., Mowszowicz, I., Chaussain, J.-L., Young, J., Morel, Y., Schaison, G. <strong>Different phenotypes in a family with androgen insensitivity caused by the same M780I point mutation in the androgen receptor gene.</strong> J. Clin. Endocr. Metab. 81: 2994-2998, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8768864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8768864</a>] [<a href="https://doi.org/10.1210/jcem.81.8.8768864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8768864">Rodien et al. (1996)</a> reported striking variations in the phenotypes of 3 related patients with a mutation in the AR gene (M780I; <a href="#0039">313700.0039</a>). Two of the affected family members had a feminine phenotype with Tanner stage 2 pubic hair, suggesting nearly complete androgen insensitivity. The third subject was male with perineoscrotal hypospadias and cryptorchidism, suggesting reduced but residual androgen sensitivity. Genital skin fibroblasts were analyzed for 5-alpha-reductase activity, and the binding capacity of the androgen receptor was higher in the male than in the 2 patients with female phenotypes. That the same mutation in different affected 46,XY members of the same family can cause variable clinical phenotypes suggests that the AR genotype does not accurately predict the phenotype in all families with androgen insensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8768864" 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="#70" class="mim-tip-reference" title="Jakubiczka, S., Nedel, S., Werder, E. A., Schleiermacher, E., Theile, U., Wolff, G., Wieacker, P. <strong>Mutations of the androgen receptor gene in patients with complete androgen insensitivity.</strong> Hum. Mutat. 9: 57-61, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8990010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8990010</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:1<57::AID-HUMU10>3.0.CO;2-O" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8990010">Jakubiczka et al. (1997)</a> identified mutations in the AR gene in 7 of 14 patients affected with complete androgen insensitivity. The authors made the following conclusions: major structural abnormalities such as deletions have been reported in only a few cases of CAIS. When both DNA- and steroid-binding domains are deleted, complete androgen resistance results. Minor structural abnormalities such as deletions or insertions of 1 or a few nucleotides are also rare. If the reading frame is disturbed, CAIS results, as is the case in the testicular feminization mouse. Single-base mutations are the most common type in the AR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8990010" 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>Premature stop codons of the AR gene are usually associated with complete androgen insensitivity syndrome. <a href="#60" class="mim-tip-reference" title="Holterhus, P.-M., Bruggenwirth, H. T., Hiort, O., Kleinkauf-Houcken, A., Kruse, K., Sinnecker, G. H. G., Brinkmann, A. O. <strong>Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 82: 3584-3589, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9360511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9360511</a>] [<a href="https://doi.org/10.1210/jcem.82.11.4375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9360511">Holterhus et al. (1997)</a> identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene (<a href="#0042">313700.0042</a>) who presented with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. Examination of the sequencing gel identified a wildtype allele, indicating mosaicism. In addition, elimination of the unique AftII recognition site induced by the mutation was incomplete, thus confirming mosaicism. Normal androgen binding studies demonstrated expression of the wildtype AR in the patient's genital skin fibroblasts. <a href="#60" class="mim-tip-reference" title="Holterhus, P.-M., Bruggenwirth, H. T., Hiort, O., Kleinkauf-Houcken, A., Kruse, K., Sinnecker, G. H. G., Brinkmann, A. O. <strong>Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 82: 3584-3589, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9360511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9360511</a>] [<a href="https://doi.org/10.1210/jcem.82.11.4375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9360511">Holterhus et al. (1997)</a> concluded that somatic mosaicism of the AR gene shifts the phenotype to a higher degree of virilization than expected from the genotype of the mutant allele alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9360511" 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="#118" class="mim-tip-reference" title="McPhaul, M. J., Schweikert, H.-U., Allman, D. R. <strong>Assessment of androgen receptor function in genital skin fibroblasts using a recombinant adenovirus to deliver an androgen-responsive reporter gene.</strong> J. Clin. Endocr. Metab. 82: 1944-1948, 1997. Note: Erratum: J. Clin. Endocr. Metab. 82: 2670 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9177411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9177411</a>] [<a href="https://doi.org/10.1210/jcem.82.6.3966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9177411">McPhaul et al. (1997)</a> used a recombinant adenovirus to deliver an androgen-responsive gene in fibroblast cultures in order to assay AR function in normal subjects and patients with different forms of androgen resistance. They studied 3 groups of patients with known or suspected defects in AR function, including those with Reifenstein syndrome, spinobulbar muscular atrophy, and severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal controls and that of patients with complete testicular feminization. The authors concluded that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including 2 with a normal AR gene sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9177411" 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="#58" class="mim-tip-reference" title="Hiort, O., Sinnecker, G. H. G., Holterhus, P.-M., Nitsche, E. M., Kruse, K. <strong>Inherited and de novo androgen receptor gene mutations: investigation of single-case families.</strong> J. Pediat. 132: 939-943, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9627582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9627582</a>] [<a href="https://doi.org/10.1016/s0022-3476(98)70387-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9627582">Hiort et al. (1998)</a> demonstrated that de novo and, in particular, somatic new mutations, occur at an unexpectedly high rate in AIS. In the AR gene mutation database maintained in Montreal, <a href="#47" class="mim-tip-reference" title="Gottlieb, B., Beitel, L. K., Trifiro, M. A. <strong>Variable expressivity and mutation databases: the androgen receptor gene mutations database.</strong> Hum. Mutat. 17: 382-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11317353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11317353</a>] [<a href="https://doi.org/10.1002/humu.1113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11317353">Gottlieb et al. (2001)</a> found 25 cases where different degrees of androgen insensitivity were caused by identical mutations in the AR gene. In 5 of these cases, the phenotypic variability was due to somatic mosaicism, that is, somatic mutations that occurred in only certain cells of androgen-sensitive tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11317353+9627582" 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="#59" class="mim-tip-reference" title="Holterhus, P. M., Sinnecker, G. H. G., Wollmann, H. A., Struve, D., Homburg, N., Kruse, K., Hiort, O. <strong>Expression of two functionally different androgen receptors in a patient with androgen insensitivity.</strong> Europ. J. Pediat. 158: 702-706, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485299</a>] [<a href="https://doi.org/10.1007/s004310051183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485299">Holterhus et al. (1999)</a> reported a 46,XY newborn with ambiguous genitalia and mutation in the AR gene (<a href="#0005">313700.0005</a>). Direct DNA sequencing and only incomplete NlaIII digestion of a genomic DNA/PCR fragment containing the mutation displayed the coexistence of mutant and wildtype androgen receptor alleles. Because the patient was the only affected family member and because only the wildtype androgen receptor DNA sequence was present in the mother, <a href="#59" class="mim-tip-reference" title="Holterhus, P. M., Sinnecker, G. H. G., Wollmann, H. A., Struve, D., Homburg, N., Kruse, K., Hiort, O. <strong>Expression of two functionally different androgen receptors in a patient with androgen insensitivity.</strong> Europ. J. Pediat. 158: 702-706, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485299</a>] [<a href="https://doi.org/10.1007/s004310051183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485299">Holterhus et al. (1999)</a> concluded that the mutation had occurred de novo at the postzygotic stage, leading to somatic mosaicism. Analysis of methyltrienolone binding on the patient's cultured genital skin fibroblasts revealed the expression of 2 functionally different androgen receptors. This finding confirmed somatic mosaicism in the patient and indicated that the most likely molecular mechanism responsible for the unexpectedly strong virilization of the proband is the androgen action through the wildtype AR expressed by part of the somatic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10485299" 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="#62" class="mim-tip-reference" title="Holterhus, P.-M., Wiebel, J., Sinnecker, G. H. G., Bruggenwirth, H. T., Sippell, W. G., Brinkmann, A. O., Kruse, K., Hiort, O. <strong>Clinical and molecular spectrum of somatic mosaicism in androgen insensitivity syndrome.</strong> Pediat. Res. 46: 684-690, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10590024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10590024</a>] [<a href="https://doi.org/10.1203/00006450-199912000-00009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10590024">Holterhus et al. (1999)</a> presented the clinical and molecular spectrum of somatic mosaicism in 5 patients. They suggested that functionally relevant expression of the wildtype androgen receptor needs to be considered in all mosaic individuals and that treatment should be adjusted accordingly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10590024" 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="#61" class="mim-tip-reference" title="Holterhus, P.-M., Sinnecker, G. H. G., Hiort, O. <strong>Phenotypic diversity and testosterone-induced normalization of mutant L712F androgen receptor function in a kindred with androgen insensitivity.</strong> J. Clin. Endocr. Metab. 85: 3245-3250, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10999816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10999816</a>] [<a href="https://doi.org/10.1210/jcem.85.9.6812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10999816">Holterhus et al. (2000)</a> reported a family with 4 affected individuals, 3 brothers and their uncle, displaying strikingly different external genitalia. They detected the same leu712-to-phe (L712F; <a href="#0050">313700.0050</a>) AR mutation in each subject. They demonstrated that the 712F AR could switch its function from subnormal to normal within the physiologic concentration range of testosterone. The authors concluded that, taking into account the well-documented individual and time-dependent variation in testosterone concentration in early fetal development, their observations illustrated the potential impact of varying ligand concentrations for distinct cases of phenotypic variability in AIS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10999816" 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="#114" class="mim-tip-reference" title="McPhaul, M. J., Griffin, J. E. <strong>Male pseudohermaphroditism caused by mutations of the human androgen receptor.</strong> J. Clin. Endocr. Metab. 84: 3435-3441, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10522976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10522976</a>] [<a href="https://doi.org/10.1210/jcem.84.10.6121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10522976">McPhaul and Griffin (1999)</a> reviewed the spectrum of AR defects that cause male phenotypic abnormalities, as well as the clinical characteristics of the heterogeneous AR mutations, including their effects on AR protein structure and their frequencies and gene locations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10522976" 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="#147" class="mim-tip-reference" title="Poujol, N., Lumbroso, S., Terouanne, B., Lobaccaro, J.-M. A., Bourguet, W., Sultan, C. <strong>Pathophysiology of androgen insensitivity syndromes: molecular and structural approaches of natural and engineered androgen receptor mutations at amino acid 743.</strong> J. Clin. Endocr. Metab. 87: 5793-5800, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12466388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12466388</a>] [<a href="https://doi.org/10.1210/jc.2002-020491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12466388">Poujol et al. (2002)</a> integrated clinical, molecular, and structural data in an investigation into the characteristics of AR ligand binding and activation. They looked for residues substituted in AIS that are conserved among the different AR species but that diverge in the other steroid receptors, thus suggesting a role in androgen-binding specificity. Of the residues fitting these characteristics, they focused on the glycine at position 743, for which the natural substitutions glutamic acid (G743E; <a href="#0057">313700.0057</a>) and valine (G743V; <a href="#0056">313700.0056</a>) have been associated with different androgen resistance phenotypes. The consequences of both substitutions were evaluated along with those of a manufactured minimal glycine-to-alanine mutation. The gradual impairment of binding and trans-activation efficiencies in AR mutants ranging from alanine to valine and subsequently glutamic acid were highlighted by in vitro experiments. Structural analyses showed the consequences of these substitutions at the atomic level and suggested a difference in local organization among the nuclear receptor superfamily. The authors concluded that this integrative approach provides a useful tool for further investigations into the AR structure-function relationship in AIS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12466388" 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="#192" class="mim-tip-reference" title="Xu, W., Robert, C., Thornton, P. S., Spinner, N. B. <strong>Complete androgen insensitivity syndrome due to X chromosome inversion: a clinical report.</strong> Am. J. Med. Genet. 120A: 434-436, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12838569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12838569</a>] [<a href="https://doi.org/10.1002/ajmg.a.20043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12838569">Xu et al. (2003)</a> described a 3-month-old girl with CAIS in whom the diagnosis was made during elective repair of inguinal hernia, which had been noted shortly after birth. She had a 46,XY karyotype with inversion of the X chromosome with one break disrupting the AR gene. Curiously, the phenotypically normal mother also carried the inversion in one X chromosome; a maternal aunt had CAIS and a 46,inv(X),Y karyotype. At the age of 5 years this aunt had undergone repair of inguinal hernias, at which time testes were identified. She underwent gonadectomy 1 year later because of concerns of potential malignancy. At age 16 years she had primary amenorrhea and a height of 180 cm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12838569" 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="#119" class="mim-tip-reference" title="Melo, K. F. S., Mendonca, B. B., Billerbeck, A. E. C., Costa, E. M. F., Inacio, M., Silva, F. A. Q., Leal, A. M. O., Latronico, A. C., Arnhold, I. J. P. <strong>Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene.</strong> J. Clin. Endocr. Metab. 88: 3241-3250, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843171</a>] [<a href="https://doi.org/10.1210/jc.2002-021658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843171">Melo et al. (2003)</a> studied 32 subjects with male pseudohermaphroditism due to androgen insensitivity syndrome from 20 families, 9 with CAIS and 11 with PAIS. They analyzed the entire coding region of the androgen receptor gene, and found mutations in all families with CAIS and in 8 of the 11 families with PAIS. They identified 15 different mutations, including 5 that had not been described. They compared detailed clinical and hormonal features with genotype in 25 subjects with AIS and confirmed these by mutation analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843171" 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="#146" class="mim-tip-reference" title="Pitteloud, N., Villegas, J., Dwyer, A. A., Crowley, W. F., Jr., McPhaul, M. J., Hayes, F. J. <strong>Acute stress masking the biochemical phenotype of partial androgen insensitivity syndrome in a patient with a novel mutation in the androgen receptor.</strong> J. Clin. Endocr. Metab. 89: 1053-1058, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001585</a>] [<a href="https://doi.org/10.1210/jc.2003-031373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15001585">Pitteloud et al. (2004)</a> reported a 61-year-old man with androgen insensitivity and coincidental functional hypogonadotropic hypogonadism. While functional hypogonadotropic hypogonadism is not a well-recognized entity in males, major stress has been reported to cause transient suppression of the hypothalamic-pituitary-gonadal axis in men. The patient was noted to have undervirilization, minimal pubertal development, hypogonadal testosterone, and low gonadotropin levels consistent with congenital hypogonadotropic hypogonadism during a hospital admission for myocardial infarction. The patient was found to have PAIS due to a ser740-to-cys mutation (<a href="#0059">313700.0059</a>) in the ligand-binding domain of the AR. Subsequent studies confirmed that he had the characteristic gonadotropin and sex steroid abnormalities of PAIS. The authors concluded that this was the first reported case of PAIS presenting with a reversible hypogonadotropic biochemical profile triggered by an acute illness and corticosteroid therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15001585" 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="#82" class="mim-tip-reference" title="Kohler, B., Lumbroso, S., Leger, J., Audran, F., Grau, E. S., Kurtz, F., Pinto, G., Salerno, M., Semitcheva, T., Czernichow, P., Sultan, C. <strong>Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling.</strong> J. Clin. Endocr. Metab. 90: 106-111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15522944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15522944</a>] [<a href="https://doi.org/10.1210/jc.2004-0462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15522944">Kohler et al. (2005)</a> noted that in 70% of AIS cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life, because both mutant and wildtype receptors are expressed, and genetic counseling. The authors reported 6 patients with AIS due to somatic mutations of the AR and 1 mother with somatic mosaicism who transmitted the mutation twice. Of the 4 patients with PAIS, 3 presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wildtype AR for virilization because the same mutations, when they are inherited, lead to CAIS. They also reported 2 novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wildtype receptor does not always lead to virilization. When a germline de novo AR mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15522944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Spinal and Bulbar Muscular Atrophy</em></strong></p><p>
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<a href="#85" class="mim-tip-reference" title="La Spada, A., Fischbeck, K. H. <strong>Androgen receptor gene defect in X-linked spinal and bulbar muscular atrophy. (Abstract)</strong> Am. J. Hum. Genet. 49 (suppl.): 20, 1991."None>La Spada and Fischbeck (1991)</a> and <a href="#87" class="mim-tip-reference" title="La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E., Fischbeck, K. H. <strong>Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.</strong> Nature 352: 77-79, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2062380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2062380</a>] [<a href="https://doi.org/10.1038/352077a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2062380">La Spada et al. (1991)</a> presented evidence that X-linked spinal and bulbar muscular atrophy (SBMA; <a href="/entry/313200">313200</a>) is due to a mutation in the polyglutamine tract encoded by the first exon of the AR gene (<a href="#0014">313700.0014</a>). The mutations consisted of increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disorder, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses; maximum lod score = 13.2 at theta = 0. Eleven different disease alleles were observed, indicating that the association was not likely to represent linkage disequilibrium. As reviewed by <a href="#51" class="mim-tip-reference" title="Griffin, J. E. <strong>Androgen resistance--the clinical and molecular spectrum.</strong> New Eng. J. Med. 326: 611-618, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734252</a>] [<a href="https://doi.org/10.1056/NEJM199202273260906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1734252">Griffin (1992)</a>, the 'clinical spectrum' of androgen resistance already included infertile male syndrome and undervirilized male syndrome; the new finding extended the spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2062380+1734252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Caskey, C. T., Pizzuti, A., Fu, Y.-H., Fenwick, R. G., Jr., Nelson, D. L. <strong>Triplet repeat mutations in human disease.</strong> Science 256: 784-789, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1589758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1589758</a>] [<a href="https://doi.org/10.1126/science.1589758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1589758">Caskey et al. (1992)</a> reviewed triplet repeat mutations identified in 2 of the most common heritable disorders, fragile X syndrome (<a href="/entry/300624">300624</a>) and myotonic dystrophy (<a href="/entry/160900">160900</a>), and in SBMA. Other similarities to the fragile X syndrome and myotonic dystrophy were pointed out by <a href="#10" class="mim-tip-reference" title="Biancalana, V., Serville, F., Pommier, J., Julien, J., Hanauer, A., Mandel, J. L. <strong>Moderate instability of the trinucleotide repeat in spinobulbar muscular atrophy.</strong> Hum. Molec. Genet. 1: 255-258, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303195</a>] [<a href="https://doi.org/10.1093/hmg/1.4.255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303195">Biancalana et al. (1992)</a> in a family with affected members in 4 generations: the mutant allele was unstable upon transmission from parent to child, with a documented variation from 46 to 53 CAG repeats and a tendency to increase in size (7 increases and a single decrease in 17 events), which appeared stronger upon transmission from a male than from a female. There was also evidence for limited somatic instability of the abnormal allele, with observable variation of up to 2 to 3 repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1589758+1303195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prostate Cancer</em></strong></p><p>
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In 1 of 26 specimens of untreated organ-confined stage B prostate cancer, <a href="#134" class="mim-tip-reference" title="Newmark, J. R., Hardy, D. O., Tonb, D. C., Carter, B. S., Epstein, J. I., Isaacs, W. B., Brown, T. R., Barrack, E. R. <strong>Androgen receptor gene mutations in human prostate cancer.</strong> Proc. Nat. Acad. Sci. 89: 6319-6323, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1631125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1631125</a>] [<a href="https://doi.org/10.1073/pnas.89.14.6319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1631125">Newmark et al. (1992)</a> identified a somatic mutation in the AR gene (<a href="#0013">313700.0013</a>) in a highly conserved region within the hormone-binding domain. An abundance of the mutated fragment indicated its presence in cells with a growth advantage. The authors postulated that somatic mutation in the AR gene leading to persistent expression could give rise to androgen-independent prostate cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1631125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The length of a polymorphic CAG repeat sequence occurring in the androgen receptor gene is inversely correlated with transcriptional activity by the androgen receptor. Men who possess exceptionally long CAG repeat lengths experience clinical androgen insensitivity, presumably related to reduced transcriptional activity of the receptor. Prostate carcinogenesis is dependent on androgens. Because shorter CAG repeat lengths are associated with high transcriptional activity of AR, <a href="#68" class="mim-tip-reference" title="Irvine, R. A., Yu, M. C., Ross, R. K., Coetzee, G. A. <strong>The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer.</strong> Cancer Res. 55: 1937-1940, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728763</a>]" pmid="7728763">Irvine et al. (1995)</a> proposed that men with shorter repeat lengths will be at higher risk for prostate cancer. Some indirect evidence is consistent with this hypothesis. African Americans, who have generally shorter CAG repeat lengths in the AR gene, have a higher incidence and mortality rate from prostate cancer (<a href="#33" class="mim-tip-reference" title="Coetzee, G. A., Ross, R. K. <strong>Re: Prostate cancer and the androgen receptor. (Letter)</strong> J. Nat. Cancer Inst. 86: 872-873, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8182772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8182772</a>] [<a href="https://doi.org/10.1093/jnci/86.11.872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8182772">Coetzee and Ross, 1994</a>). Moreover, because of X linkage, a history of disease in a brother carries greater risk than paternal history. Against this background, <a href="#46" class="mim-tip-reference" title="Giovannucci, E., Stampfer, M. J., Krithivas, K., Brown, M., Dahl, D., Brufsky, A., Talcott, J., Hennekens, C. H., Kantoff, P. W. <strong>The CAG repeat within the androgen receptor gene and its relationship to prostate cancer.</strong> Proc. Nat. Acad. Sci. 94: 3320-3323, 1997. Note: Erratum: Proc. Nat. Acad. Sci. 94: 8272 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9096391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9096391</a>] [<a href="https://doi.org/10.1073/pnas.94.7.3320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9096391">Giovannucci et al. (1997)</a> conducted within the Physician's Health Study a nested case-controlled study of 587 newly diagnosed cases of prostate cancer detected between 1982 and 1995, and 588 controls without prostate cancer. They found an association between fewer androgen receptor gene CAG repeats and higher risk of total prostate cancer. In particular, a shorter CAG repeat sequence was associated with cancers characterized by extraprostatic extension, distant metastases, or high histologic grade. Variability in the CAG repeat length was not associated with low-grade or low-stage disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8182772+7728763+9096391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To test for an association between clinical parameters of human prostate cancer and CAG repeat length, <a href="#55" class="mim-tip-reference" title="Hardy, D. O., Scher, H. I., Bogenreider, T., Sabbatini, P., Zhang, Z.-F., Nanus, D. M., Catterall, J. F. <strong>Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset.</strong> J. Clin. Endocr. Metab. 81: 4400-4405, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954049</a>] [<a href="https://doi.org/10.1210/jcem.81.12.8954049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954049">Hardy et al. (1996)</a> analyzed normal lymphocyte DNA from 109 patients. The median age of patients was 63 years (range, 42 to 83), with 104 Caucasian, 2 African American, 1 Asian, and 2 of other racial origin. The median repeat length was 25, 22, 22, and 23 for patients presenting with stage A, B, C, and D disease, respectively. A significant correlation between CAG repeat length and age at onset was observed, whereas correlations with stage, level of prostate-specific antigen at diagnosis, and time to prostate-specific antigen relapse were not significant. Shorter CAG repeat lengths may be associated with the development of prostate cancer in men at a younger age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8954049" 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="#26" class="mim-tip-reference" title="Chang, B., Zheng, S. L., Hawkins, G. A., Isaacs, S. D., Wiley, K. E., Turner, A., Carpten, J. D., Bleecker, E. R., Walsh, P. C., Trent, J. M., Meyers, D. A., Isaacs, W. B., Xu, J. <strong>Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk.</strong> Hum. Genet. 110: 122-129, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11935317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11935317</a>] [<a href="https://doi.org/10.1007/s00439-001-0662-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11935317">Chang et al. (2002)</a> found significantly increased frequencies of AR alleles carrying 16 or less GGC repeats in 159 independent hereditary prostate cancer cases (71%) and 245 sporadic prostate cancer cases (68%) compared with 211 controls (59%). No evidence for association between CAG repeats and prostate cancer risk was observed. Similar results were found with a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11935317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other Male-Specific Phenotypes Associated with Expanded Polyglutamine Repeat in the AR Gene</em></strong></p><p>
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<a href="#104" class="mim-tip-reference" title="Macke, J. P., Hu, N., Hu, S., Bailey, M., King, V. L., Brown, T., Hamer, D., Nathans, J. <strong>Sequence variation in the androgen receptor gene is not a common determinant of male sexual orientation.</strong> Am. J. Hum. Genet. 53: 844-852, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213813</a>]" pmid="8213813">Macke et al. (1993)</a> used 3 complementary approaches to test the hypothesis that sequence variation in the AR gene plays a causal role in the development of male sexual orientation: linkage analysis using pairs of homosexual brothers, measurement of repeat lengths in tracts of single amino acids that are known to be highly variable in the population, and direct screening for nucleotide sequence changes. The analyses showed that homosexual brothers are as likely to be discordant as concordant for androgen receptor alleles; there are no large-scale differences between the distributions of polyglycine or polyglutamine tract lengths in the homosexual and control groups; and coding region sequence variation is not commonly found within the androgen receptor gene of homosexual men. The denaturing gradient gel electrophoresis (DGGE) screen identified 2 rare amino acid substitutions, ser205-to-arg and glu793-to-asp, the biologic significance of which was unknown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8213813" 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="#196" class="mim-tip-reference" title="Zhang, L., Leeflang, E. P., Yu, J., Arnheim, N. <strong>Studying human mutations by sperm typing: instability of CAG trinucleotide repeats in the human androgen receptor gene.</strong> Nature Genet. 7: 531-535, 1994. Note: Erratum: Nature Genet. 8: 203 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951325</a>] [<a href="https://doi.org/10.1038/ng0894-531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951325">Zhang et al. (1994)</a> studied the instability of CAG trinucleotide repeats in the human AR gene by typing approximately 4,300 human sperm. While the mutation rate for 20- to 22-repeat alleles was similar to that shown by family analysis, alleles with 28 to 31 repeats had a 4.4 times greater rate of mutation, with contractions outnumbering expansions 9 to 1. The authors suggested that disease-causing alleles may be susceptible to 2 different mutational mechanisms, one primarily resulting in contraction and another leading to trinucleotide expansion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7951325" 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="#174" class="mim-tip-reference" title="Tut, T. G., Ghadessy, F. J., Trifiro, M. A., Pinsky, L., Yong, E. L. <strong>Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility.</strong> J. Clin. Endocr. Metab. 82: 3777-3782, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9360540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9360540</a>] [<a href="https://doi.org/10.1210/jcem.82.11.4385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9360540">Tut et al. (1997)</a> hypothesized that changes in the AR gene could have a role in some cases of male infertility associated with impaired spermatogenesis. To test this hypothesis, they examined the lengths of the polyglutamine and polyglycine repeats in 153 patients with defective sperm production and compared them to those of 72 normal controls of proven fertility. There was no significant association between the polyglycine tract and infertility. However, patients with 28 or more glutamines in their AR had a greater than 4-fold (95% CI, 4.9 to 3.2) increased risk of impaired spermatogenesis, and the more severe the spermatogenic defect, the higher the proportion of patients with a longer Gln repeat. The risk of defective spermatogenesis was halved when the polyglutamine tract was short (23 or less glutamines). Whole-cell transfection experiments using AR constructs harboring 15, 20, or 31 Gln repeats and a luciferase reporter gene with an androgen response element promoter confirmed an inverse relationship between Gln number and trans-regulatory activity. Immunoblot analyses indicated that the reduced androgenicity of the ARs with longer Gln repeats was unlikely to be due to a change in AR protein levels. The authors concluded that there is a direct relation between the length of the AR polyglutamine tract and the risk of defective spermatogenesis that is attributable to the decreased AR functional competence that occurs with longer Gln tracts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9360540" 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="#37" class="mim-tip-reference" title="Dowsing, A. T., Yong, E. L., Clark, M., McLachlan, R. I., de Kretser, D. M., Trounson, A. O. <strong>Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene.</strong> Lancet 354: 640-643, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10466666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10466666</a>] [<a href="https://doi.org/10.1016/s0140-6736(98)08413-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10466666">Dowsing et al. (1999)</a> characterized the androgen gene in 35 male patients with infertility. Thirty had idiopathic azoospermia or oligozoospermia, and these men were found to have significantly longer CAG repeat tracts than controls (mean 23.2 vs 20.5; p = 0.0001). The odds of having CAG repeat lengths of 20 were 6-fold higher for fertile men than for men with a spermatogenic disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10466666" 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="#84" class="mim-tip-reference" title="Kooy, R. F., Reyniers, E., Storm, K., Vits, L., van Velzen, D., de Ruiter, P. E., Brinkmann, A. O., de Paepe, A., Willems, P. J. <strong>CAG repeat contraction in the androgen receptor gene in three brothers with mental retardation.</strong> Am. J. Med. Genet. 85: 209-213, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398229</a>]" pmid="10398229">Kooy et al. (1999)</a> reported 3 brothers with mental retardation, behavior problems, marfanoid habitus, and normal male genitalia who had a contracted CAG repeat in their AR genes (8 repeats compared to the 11 to 33 repeats normally seen). The authors concluded that a causative relationship between a short CAG repeat in the AR gene and the observed phenotype could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10398229" 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="#95" class="mim-tip-reference" title="Lim, H. N., Chen, H., McBride, S., Dunning, A. M., Nixon, R. M., Hughes, I. A., Hawkins, J. R. <strong>Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males.</strong> Hum. Molec. Genet. 9: 829-834, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749991</a>] [<a href="https://doi.org/10.1093/hmg/9.5.829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10749991">Lim et al. (2000)</a> examined whether longer AR(Gln)n repeats are associated with moderate to severe undermasculinization. Clinical features among the 78 undermasculinized 46,XY males studied included partly fused or unfused scrotum, micropenis, and hypospadias. The average AR(Gln)n length of the undermasculinized group (median 25, interquartile range 23-26) was significantly greater than that of the 850 controls (median 23, interquartile range 22-26, p = 0.002). The odds ratio of having 23 or more repeats (as opposed to 22 or fewer repeats) in the undermasculinized group was 2.51 (95% CI, 1.41-4.48). The estimated increase in the odds ratio for each additional repeat was 9.07%. The authors hypothesized that the association of undermasculinized genitalia and isolated male factor infertility with AR(Gln)n length provided further evidence that they may represent different degrees of severity of the same disease process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The fact that sperm numbers range from 20 to 300 million/mL in normal men without any indication of changed endocrine parameters led <a href="#177" class="mim-tip-reference" title="Von Eckardstein, S., Syska, A., Gromoll, J., Kamischke, A., Simoni, M., Nieschlag, E. <strong>Inverse correlation between sperm concentration and number of androgen receptor CAG repeats in normal men.</strong> J. Clin. Endocr. Metab. 86: 2585-2590, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397858</a>] [<a href="https://doi.org/10.1210/jcem.86.6.7608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11397858">von Eckardstein et al. (2001)</a> to assume that genetic variability of transduction of androgen signaling could be important. They compared the variable number of CAG repeats in the AR with sperm concentrations in men with normal ejaculate parameters (62 fathers and 69 volunteers participating in clinical trials). In multivariate analysis, CAG repeat length did not differ between the volunteers and the fathers, but was significantly correlated to sperm concentrations with a coefficient of -0.25. When compared with a group of infertile men, 14 with and 30 without a family history of infertility, no such correlation was found. The authors concluded that men with short CAG repeats have the highest sperm output within the normal fertile population, and that AR polymorphisms contribute to the efficiency of spermatogenesis in normal men, but do not play a predominant role in male infertility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11397858" 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="#200" class="mim-tip-reference" title="Zitzmann, M., Brune, M., Kornmann, B., Gromoll, J., von Eckardstein, S., von Eckardstein, A., Nieschlag, E. <strong>The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity.</strong> J. Clin. Endocr. Metab. 86: 4867-4873, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11600555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11600555</a>] [<a href="https://doi.org/10.1210/jcem.86.10.7889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11600555">Zitzmann et al. (2001)</a> investigated the interactions among the CAG polymorphism, serum levels of sex hormones, cardiovascular risk factors, and flow-mediated and nitrate-induced vasodilatation of the brachial artery in 110 healthy males aged 25 to 50 years. The number of CAG repeats had no significant correlations with serum concentrations of total or free testosterone. Stepwise multiple regression analysis revealed positive correlations of the number of CAG repeats with serum levels of high density lipoprotein (HDL) cholesterol and flow-mediated vasodilatation. The association of CAG repeats with HDL cholesterol was independent of body fat content and serum levels of free testosterone, both of which had significant negative correlations with HDL cholesterol. The authors concluded that a low number of CAG repeats in the AR gene implies a greater chance for low levels of HDL cholesterol and reduced endothelial response to ischemia, which are important risk factors for coronary heart disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11600555" 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="#201" class="mim-tip-reference" title="Zitzmann, M., Depenbusch, M., Gromoll, J., Nieschlag, E. <strong>Prostate volume and growth in testosterone-substituted hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: a longitudinal pharmacogenetic study.</strong> J. Clin. Endocr. Metab. 88: 2049-2054, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12727953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12727953</a>] [<a href="https://doi.org/10.1210/jc.2002-021947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12727953">Zitzmann et al. (2003)</a> investigated the effect of AR CAG(n) repeat length on prostate volume and growth in testosterone-substituted hypogonadal men, 69 with primary hypogonadism and 62 with secondary hypogonadism. Average prostate size increased from 15.8 +/- 6.1 ml to 23.0 +/- 6.8 ml. ANOVA including covariates revealed initial prostate size to be dependent on age and baseline testosterone levels but not on number of (CAG)n. Prostate growth per year and absolute prostate size under substituted testosterone levels were strongly dependent on (CAG)n, with lower treatment effects in longer repeats. The odds ratio for men with fewer than 20 (CAG)n, compared with those with 20 or more (CAG)n, to develop a prostate size of at least 30 ml under testosterone substitution, was 8.7 (95% CI, 3.1-24.3; p less than 0.001). This observation was strongly age-dependent, with a more pronounced odds ratio in men older than 40 years. The authors concluded that this first pharmacogenetic study on androgen substitution in hypogonadal men demonstrated a marked influence of the AR gene (CAG)n polymorphism on prostate growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12727953" 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="#202" class="mim-tip-reference" title="Zitzmann, M., Depenbusch, M., Gromoll, J., Nieschlag, E. <strong>X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients.</strong> J. Clin. Endocr. Metab. 89: 6208-6217, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579779</a>] [<a href="https://doi.org/10.1210/jc.2004-1424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579779">Zitzmann et al. (2004)</a> analyzed phenotypic and clinical traits in 77 newly diagnosed and untreated patients with Klinefelter syndrome and a 47,XXY karyotype in regard to the putative influence of X chromosome inactivation and AR (CAG)n length. In 48 men who were hypogonadal and received T substitution therapy, pharmacogenetic effects were investigated. The shorter (CAG)n allele was preferentially inactive. (CAG)n length was positively associated with body height. Bone density and the relation of arm span to body height were inversely related to (CAG)n length. The presence of long (CAG)n was predictive for gynecomastia and smaller testes, whereas short (CAG)n were associated with a stable partnership and professions requiring higher standards of education also when corrected for family background. There was a trend for men with longer (CAG)n to be diagnosed earlier in life. Under testosterone substitution, men with shorter (CAG)n exhibited a more profound suppression of luteinizing hormone (LH; see <a href="/entry/152780">152780</a>) levels, augmented prostate growth, and higher hemoglobin concentrations. The effects of testosterone substitution are pharmacogenetically modified, and this finding is magnified by preferential inactivation of the more functional short (CAG)n allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579779" 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="#199" class="mim-tip-reference" title="Zinn, A. R., Ramos, P., Elder, F. F., Kowal, K., Samango-Sprouse, C., Ross, J. L. <strong>Androgen receptor CAG(n) repeat length influences phenotype of 47,XXY (Klinefelter) syndrome.</strong> J. Clin. Endocr. Metab. 90: 5041-5046, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15956082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15956082</a>] [<a href="https://doi.org/10.1210/jc.2005-0432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15956082">Zinn et al. (2005)</a> investigated the role of the AR CAG(n) repeat length to phenotypic variability in Klinefelter syndrome. The CAG(n) repeat length was inversely correlated with penile length, a biologic indicator of early androgen action. Mosaicism, imprinting, and skewed X inactivation did not account for the variability of the Klinefelter syndrome phenotype. <a href="#199" class="mim-tip-reference" title="Zinn, A. R., Ramos, P., Elder, F. F., Kowal, K., Samango-Sprouse, C., Ross, J. L. <strong>Androgen receptor CAG(n) repeat length influences phenotype of 47,XXY (Klinefelter) syndrome.</strong> J. Clin. Endocr. Metab. 90: 5041-5046, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15956082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15956082</a>] [<a href="https://doi.org/10.1210/jc.2005-0432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15956082">Zinn et al. (2005)</a> concluded that normal genetic variation in the AR coding sequence may be clinically significant in the setting of early testicular failure and subnormal circulating testosterone levels, as occurs in Klinefelter syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15956082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association with Female-Specific Phenotypes</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Calvo, R. M., Asuncion, M., Sancho, J., San Millan, J. L., Escobar-Morreale, H. F. <strong>The role of the CAG repeat polymorphism in the androgen receptor gene and of skewed X-chromosome inactivation, in the pathogenesis of hirsutism.</strong> J. Clin. Endocr. Metab. 85: 1735-1740, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10770223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10770223</a>] [<a href="https://doi.org/10.1210/jcem.85.4.6561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10770223">Calvo et al. (2000)</a> found no association between the AR CAG repeat number and hirsutism in women with or without hyperandrogenemia. Skewed X-chromosome inactivation was found in 10 (14.9%) of 67 subjects (3 with idiopathic hirsutism, 5 with hyperandrogenic hirsutism, and 2 controls; p = 0.746), which was not significant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10770223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the role of the AR CAG repeat tract in polycystic ovarian syndrome (PCOS; <a href="/entry/184700">184700</a>), <a href="#122" class="mim-tip-reference" title="Mifsud, A., Ramirez, S., Yong, E. L. <strong>Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries.</strong> J. Clin. Endocr. Metab. 85: 3484-3488, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10999852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10999852</a>] [<a href="https://doi.org/10.1210/jcem.85.9.6832" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10999852">Mifsud et al. (2000)</a> measured its length in 91 patients with ultrasound diagnosis of polycystic ovaries, irregular menstrual cycles, and anovulatory infertility and compared them to 112 control subjects of proven fertility with regular menses. They compared differences in CAG length between patients whose serum testosterone levels were below the normal laboratory mean to those that were higher. There was a trend for a lower mean CAG biallelic length among anovulatory patients with serum testosterone less than 1.73 nmol/L compared with those whose testosterone was more than 1.73 nmol/L. This difference in CAG length between patients with low and high testosterone levels was highly significant when only the shorter allele of each individual was considered. Ethnic differences were also evident in the data; Indian subjects had a significantly shorter AR-CAG length compared with Chinese. The authors concluded that their data indicated an association between short CAG repeat length and the subset of anovulatory patients with low serum androgens, suggesting that the pathogenic mechanisms of polycystic ovaries in these patients could be due to the increased intrinsic androgenic activity associated with short AR alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10999852" 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="#57" class="mim-tip-reference" title="Hickey, T., Chandy, A., Norman, R. J. <strong>The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome.</strong> J. Clin. Endocr. Metab. 87: 161-165, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788641</a>] [<a href="https://doi.org/10.1210/jcem.87.1.8137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11788641">Hickey et al. (2002)</a> compared frequency distribution of CAG repeat alleles and their pattern of expression via X-inactivation analysis among 83 fertile women and 122 infertile women with PCOS, all of Australian Caucasian ethnicity. A population comparison with 831 predominantly fertile Australian women was also used. Infertile women with PCOS exhibited a greater frequency of CAG alleles or biallelic means greater than 22 repeats compared with both the fertile control group (p less than 0.05) and the general population (p less than 0.01). Preferential expression of longer CAG repeat alleles was also observed in PCOS and correlated with increased serum T. The authors concluded that the AR (CAG)n gene locus and/or its differential methylation patterns influence the disease process leading to PCOS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11788641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To elucidate the possible role of genetic variation in AR, ESR1 (<a href="/entry/133430">133430</a>), and ESR2 (<a href="/entry/601663">601663</a>) on serum androgen levels in premenopausal women, <a href="#185" class="mim-tip-reference" title="Westberg, L., Baghaei, F., Rosmond, R., Hellstrand, M., Landen, M., Jansson, M., Holm, G., Bjorntorp, P., Eriksson, E. <strong>Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women.</strong> J. Clin. Endocr. Metab. 86: 2562-2568, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397855</a>] [<a href="https://doi.org/10.1210/jcem.86.6.7614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11397855">Westberg et al. (2001)</a> studied the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ESR1 gene, and the CA repeat polymorphism of the ESR2 gene in a population-based cohort of 270 women. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH (see <a href="/entry/152780">152780</a>), than women with longer CAG repeat sequences. The CA repeat of the ESR2 gene also was associated with androgen and sex steroid hormone-binding globulin (SHBG; <a href="/entry/182205">182205</a>) levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ESR1 gene was not associated with the levels of any of the hormones measured. The authors concluded that serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ESR2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11397855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 255 Canadian women with breast cancer (<a href="/entry/114480">114480</a>) and 461 controls, <a href="#43" class="mim-tip-reference" title="Giguere, Y., Dewailly, E., Brisson, J., Ayotte, P., Laflamme, N., Demers, A., Forest, V.-I., Dodin, S., Robert, J., Rousseau, F. <strong>Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population.</strong> Cancer Res. 61: 5869-5874, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479228</a>]" pmid="11479228">Giguere et al. (2001)</a> found that those with an AR CAG repeat length of 39 or less had a significantly decreased risk for disease development (odds ratio of 0.5) compared to women with CAG repeat lengths greater than 40. The association was stronger in postmenopausal women (odds ratio of 0.3). <a href="#43" class="mim-tip-reference" title="Giguere, Y., Dewailly, E., Brisson, J., Ayotte, P., Laflamme, N., Demers, A., Forest, V.-I., Dodin, S., Robert, J., Rousseau, F. <strong>Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population.</strong> Cancer Res. 61: 5869-5874, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479228</a>]" pmid="11479228">Giguere et al. (2001)</a> concluded that short alleles of the CAG repeat were protective against breast cancer, and suggested that the protection was the consequence of increased response and sensitivity to androgens, which may inhibit the growth of breast cancer cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To test the hypothesis that risk for the development of precocious pubarche and subsequent features of ovarian hyperandrogenism might relate to genetic variation in androgen receptor sensitivity, <a href="#64" class="mim-tip-reference" title="Ibanez, L., Ong, K. K., Mongan, N., Jaaskelainen, J., Marcos, M. V., Hughes, I. A., De Zegher, F., Dunger, D. B. <strong>Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.</strong> J. Clin. Endocr. Metab. 88: 3333-3338, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843184</a>] [<a href="https://doi.org/10.1210/jc.2002-021791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843184">Ibanez et al. (2003)</a> compared CAG repeat number in Barcelona-Spanish girls who presented with precocious pubarche against Spanish controls and examined the relationship between CAG number and clinical-metabolic phenotypes of ovarian hyperandrogenism post menarche. Girls with precocious pubarche had shorter mean CAG number than controls (PP vs controls: mean, range: 21.3, 7-31 repeats vs 22.0, 15-32, p = 0.003) and greater proportion of short alleles of 20 repeats or less (37.0% vs 24.6%, p = 0.002). Among postmenarcheal girls with precocious pubarche, shorter CAG number was associated with higher 17-hydroxy-progesterone levels in response to a GNRH (<a href="/entry/152760">152760</a>) agonist, indicative of ovarian hyperandrogenism; higher testosterone levels, acne, and hirsutism scores; and more menstrual cycle irregularities. The authors concluded shorter AR gene CAG number, indicative of increased androgen sensitivity, increases risk for precocious pubarche and subsequent ovarian hyperandrogenism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To assess whether abnormalities in AR function in both peripheral blood leukocytes (PBLs) and androgen target tissues are present in children with premature pubarche, <a href="#178" class="mim-tip-reference" title="Vottero, A., Capelletti, M., Giuliodori, S., Viani, I., Ziveri, M., Neri, T. M., Bernasconi, S., Ghizzoni, L. <strong>Decreased androgen receptor gene methylation in premature pubarche: a novel pathogenetic mechanism?</strong> J. Clin. Endocr. Metab. 91: 968-972, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16403814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16403814</a>] [<a href="https://doi.org/10.1210/jc.2005-2354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16403814">Vottero et al. (2006)</a> studied 25 girls with PP, 23 prepubertal children, and 20 girls with Tanner stage II pubertal development. In PBLs from PP patients, AR gene methylation was significantly lower (p less than 0.01) than that of prepubertal children and similar to that of girls with Tanner II stage pubertal development. A negative correlation between AR gene methylation in PBLs and the age of normal children was detected. The mean number of CAG repeats was lower in PP patients than in prepubertal and Tanner stage girls, although it was within the normal range for the general population in both groups. <a href="#178" class="mim-tip-reference" title="Vottero, A., Capelletti, M., Giuliodori, S., Viani, I., Ziveri, M., Neri, T. M., Bernasconi, S., Ghizzoni, L. <strong>Decreased androgen receptor gene methylation in premature pubarche: a novel pathogenetic mechanism?</strong> J. Clin. Endocr. Metab. 91: 968-972, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16403814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16403814</a>] [<a href="https://doi.org/10.1210/jc.2005-2354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16403814">Vottero et al. (2006)</a> concluded that the increased AR activity observed in PP patients, as indicated by the reduced AR gene methylation pattern, together with the presence of shorter CAG repeats, might lead to hypersensitivity of the hair follicles to steroid hormones and therefore to the premature development of pubic hair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16403814" 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>From a study of 330 women with PCOS and 289 controls, <a href="#158" class="mim-tip-reference" title="Shah, N. A., Antoine, H. J., Pall, M., Taylor, K. D., Azziz, R., Goodarzi, M. O. <strong>Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome.</strong> J. Clin. Endocr. Metab. 93: 1939-1945, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18303071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18303071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18303071[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2008-0038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18303071">Shah et al. (2008)</a> reported that a smaller biallelic mean of CAG repeats in the AR gene was associated with increased odds of PCOS. X-chromosome inactivation was not different comparing cases with controls; however, in the subset with nonrandom inactivation, the chromosome bearing the shorter CAG allele was preferentially active in PCOS women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18303071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Chatterjee, S., Singh, R., Kadam, S., Maitra, A., Thangaraj, K., Meherji, P., Modi, D. <strong>Longer CAG repeat length in the androgen receptor gene is associated with premature ovarian failure.</strong> Hum. Reprod. 24: 3230-3235, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19684044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19684044</a>] [<a href="https://doi.org/10.1093/humrep/dep296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19684044">Chatterjee et al. (2009)</a> investigated CAG repeat number in exon 1 of the AR gene in 78 Indian women with premature ovarian failure (POF; see <a href="/entry/311360">311360</a>) and 90 controls and found that the mean CAG repeat length was significantly longer in women with POF than in controls (p less than 0.001). The 22 and 24 CAG repeat alleles were found at the highest frequency in patients (15.38% and 12.8%, respectively), although the 19 CAG repeat allele was observed at the highest frequency (12.2%) in controls. <a href="#28" class="mim-tip-reference" title="Chatterjee, S., Singh, R., Kadam, S., Maitra, A., Thangaraj, K., Meherji, P., Modi, D. <strong>Longer CAG repeat length in the androgen receptor gene is associated with premature ovarian failure.</strong> Hum. Reprod. 24: 3230-3235, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19684044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19684044</a>] [<a href="https://doi.org/10.1093/humrep/dep296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19684044">Chatterjee et al. (2009)</a> suggested that CAG repeat length might be pathogenic for POF, at least in a subset of Indian women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19684044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association with Osteoarthritis</em></strong></p><p>
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In a case-control cohort of 158 Greek patients with idiopathic osteoarthritis of the knees (see <a href="/entry/165720">165720</a>) and 193 controls, <a href="#40" class="mim-tip-reference" title="Fytili, P., Giannatou, E., Papanikolaou, V., Stripeli, F., Karachalios, T., Malizos, K., Tsezou, A. <strong>Association of repeat polymorphisms in the estrogen receptors alpha, beta, and androgen receptor genes with knee osteoarthritis.</strong> Clin. Genet. 68: 268-277, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16098017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16098017</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00495.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16098017">Fytili et al. (2005)</a> studied long (L) and short (S) alleles of the -1174(TA)n, 1092+3607(CA)n, and 172(CAG)n repeat polymorphisms of the ESR1, ESR2, and androgen receptor genes, respectively. When odds ratios were adjusted for various risk factors, it was observed that women with LL genotypes for ESR2 and AR genes showed significantly increased risk for the development of osteoarthritis (p = 0.002 and 0.001, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16098017" 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="#38" class="mim-tip-reference" title="Edwards, A., Hammond, H. A., Jin, L., Caskey, C. T., Chakraborty, R. <strong>Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups.</strong> Genomics 12: 241-253, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1740333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1740333</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90371-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1740333">Edwards et al. (1992)</a> demonstrated that the distribution of the number of CAG repeats in exon 1 of the AR gene was lowest in African Americans, intermediate in non-Hispanic whites, and highest in Asians. The distribution of allele size was bimodal in African Americans, and only in African Americans was there a deviation from Hardy-Weinberg equilibrium. <a href="#68" class="mim-tip-reference" title="Irvine, R. A., Yu, M. C., Ross, R. K., Coetzee, G. A. <strong>The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer.</strong> Cancer Res. 55: 1937-1940, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728763</a>]" pmid="7728763">Irvine et al. (1995)</a> studied the distribution of the CAG and GC microsatellite repeats in exon 1 of the AR gene in African Americans, non-Hispanic whites, and Asians (Japanese and Chinese), and confirmed the findings of <a href="#38" class="mim-tip-reference" title="Edwards, A., Hammond, H. A., Jin, L., Caskey, C. T., Chakraborty, R. <strong>Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups.</strong> Genomics 12: 241-253, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1740333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1740333</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90371-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1740333">Edwards et al. (1992)</a>. The frequency of prostate cancer (<a href="/entry/301120">301120</a>) in the 3 racial groups is inversely proportional to the length of the repeats. One of the critical functions of the product of the AR gene is to activate the expression of target genes. This transactivation activity resides in the N-terminal domain of the protein encoded in exon 1, which contains the polymorphic repeats. The smaller size of the CAG repeat is associated with a higher level of receptor transactivation function, thereby possibly resulting in a higher risk of prostate cancer. <a href="#68" class="mim-tip-reference" title="Irvine, R. A., Yu, M. C., Ross, R. K., Coetzee, G. A. <strong>The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer.</strong> Cancer Res. 55: 1937-1940, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7728763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7728763</a>]" pmid="7728763">Irvine et al. (1995)</a> noted that <a href="#157" class="mim-tip-reference" title="Schoenberg, M. P., Hakimi, J. M., Wang, S., Bova, G. S., Epstein, J. I., Fischbeck, K. H., Isaacs, W. B., Walsh, P. C., Barrack, E. R. <strong>Microsatellite mutation (CAG (24-to-18)) in the androgen receptor gene in human prostate cancer</strong> Biochem. Biophys. Res. Commun. 198: 74-80, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8292051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8292051</a>] [<a href="https://doi.org/10.1006/bbrc.1994.1011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8292051">Schoenberg et al. (1994)</a> had observed a somatic mutation resulting in a contraction of the CAG repeat from 24 to 18 in an adenocarcinoma of the prostate, and that the effects of the shorter allele were implicated in the development of the tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1740333+8292051+7728763" 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 and German populations, <a href="#34" class="mim-tip-reference" title="Correa-Cerro, L., Wohr, G., Haussler, J., Berthon, P., Drelon, E., Mangin, P., Fournier, G., Cussenot, O., Kraus, P., Just, W., Paiss, T., Cantu, J. M., Vogel, W. <strong>(CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population.</strong> Europ. J. Hum. Genet. 7: 357-362, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10234512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10234512</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10234512">Correa-Cerro et al. (1999)</a> found no association between the risk of prostate cancer and alleles of the CAG and GGC repeats in the first exon of the AR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10234512" 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="#78" class="mim-tip-reference" title="Kittles, R. A., Young, D., Weinrich, S., Hudson, J., Argyropoulos, G., Ukoli, F., Adams-Campbell, L., Dunston, G. M. <strong>Extent of linkage disequilibrium between the androgen receptor gene CAG and GGC repeats in human populations: implications for prostate cancer risk.</strong> Hum. Genet. 109: 253-261, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11702204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11702204</a>] [<a href="https://doi.org/10.1007/s004390100576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11702204">Kittles et al. (2001)</a> presented data on CAG and GGC allelic variation and linkage disequilibrium in 6 diverse populations from Africa, Asia, and North America. Populations of African descent possessed significantly shorter alleles for the 2 loci than non-African populations (p less than 0.0001). Allelic diversity for both markers was higher among African Americans than any other population, including indigenous Africans from Sierra Leone and Nigeria. Approximately 20% of CAG and GGC repeat variance was attributed to differences between populations. All non-African populations possessed the same common haplotype whereas the 3 populations of African descent possessed 3 divergent common haplotypes. Significant linkage disequilibrium was observed in the sample of healthy African Americans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11702204" 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="#122" class="mim-tip-reference" title="Mifsud, A., Ramirez, S., Yong, E. L. <strong>Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries.</strong> J. Clin. Endocr. Metab. 85: 3484-3488, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10999852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10999852</a>] [<a href="https://doi.org/10.1210/jcem.85.9.6832" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10999852">Mifsud et al. (2000)</a> found that the average biallelic mean CAG length in Chinese subjects (patients and controls) was longer than for Indians, being 23.16 +/- 0.17 and 22.08 +/- 0.5, respectively (p = 0.035). The mean length of the short allele was also different between the 2 groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10999852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Davis-Dao, C. A., Tuazon, E. D., Sokol, R. Z., Cortessis, V. K. <strong>Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis.</strong> J. Clin. Endocr. Metab. 92: 4319-4326, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17684052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17684052</a>] [<a href="https://doi.org/10.1210/jc.2007-1110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17684052">Davis-Dao et al. (2007)</a> performed a metaanalysis of data from a total of 3,027 cases and 2,722 controls extracted from 33 independent studies of the relationship between AR CAG repeat lengths and male infertility. Publication dates ranged from 1997 to 2006. Estimates of the standardized mean difference (95% confidence interval) were 0.19 (0.09-0.29) for the 33 studies and 0.31 (0.14-0.47) for a subset of 13 studies that used more stringent case and control selection criteria. Thus, in both groups, cases had statistically significantly longer CAG repeat length than controls. Publication date appeared to be a significant source of variation between studies; while repeat lengths among controls were nearly constant, the average repeat length among cases declined during the interval 1999 to 2005. The authors suggested that this may be attributable to changing patterns of referral to infertility clinics during this period, with the introduction of new therapies leading men with a wider array of conditions to seek treatment. <a href="#36" class="mim-tip-reference" title="Davis-Dao, C. A., Tuazon, E. D., Sokol, R. Z., Cortessis, V. K. <strong>Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis.</strong> J. Clin. Endocr. Metab. 92: 4319-4326, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17684052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17684052</a>] [<a href="https://doi.org/10.1210/jc.2007-1110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17684052">Davis-Dao et al. (2007)</a> concluded that their metaanalysis provided support for an association between increased androgen receptor CAG length and idiopathic male infertility, suggesting that even subtle disruptions in the androgen axis may compromise male fertility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17684052" 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="#112" class="mim-tip-reference" title="McLean, C. Y., Reno, P. L., Pollen, A. A., Bassan, A. I., Capellini, T. D., Guenther, C., Indjeian, V. B., Lim, X., Menke, D. B., Schaar, B. T., Wenger, A. M., Bejerano, G., Kingsley, D. M. <strong>Human-specific loss of regulatory DNA and the evolution of human-specific traits.</strong> Nature 471: 216-219, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21390129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21390129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21390129[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/nature09774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21390129">McLean et al. (2011)</a> identified molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. They confirmed 510 such deletions in humans, which fall almost exclusively in noncoding regions and are enriched near genes involved in steroid hormone signaling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human AR, a molecular change correlated with anatomic loss of androgen-dependent sensory vibrissae and penile spines in the human lineage. Another deletion removes a forebrain subventricular zone enhancer near the tumor suppressor gene 'growth arrest- and DNA damage-inducible, gamma' (GADD45G; <a href="/entry/604949">604949</a>), a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionarily divergence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21390129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Animal Model of Spinal and Bulbar Muscular Atrophy</em></strong></p><p>
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<a href="#86" class="mim-tip-reference" title="La Spada, A. R., Peterson, K. R., Meadows, S. A., McClain, M. E., Jeng, G., Chmelar, R. S., Haugen, H. A., Chen, K., Singer, M. J., Moore, D., Trask, B. J., Fischbeck, K. H., Clegg, C. H., McKnight, G. S. <strong>Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability.</strong> Hum. Molec. Genet. 7: 959-967, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9580659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9580659</a>] [<a href="https://doi.org/10.1093/hmg/7.6.959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9580659">La Spada et al. (1998)</a> attempted to model disease pathogenesis and repeat instability at the SBMA (<a href="/entry/313200">313200</a>) locus by creating transgenic mouse lines with yeast artificial chromosomes carrying CAG repeat expansions in the human AR gene. Transgenic mice with (CAG)45 alleles showed an approximately 10% rate of repeat length instability in transgene-positive progeny. The (CAG)45 repeat tract was significantly more unstable with maternal transmission and as the transmitting female aged. A segment of about 70 kb of the AR locus appeared to contain a cis-acting instability element. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9580659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abel, A., Walcott, J., Woods, J., Duda, J., Merry, D. E. <strong>Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice.</strong> Hum. Molec. Genet. 10: 107-116, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11152658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11152658</a>] [<a href="https://doi.org/10.1093/hmg/10.2.107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11152658">Abel et al. (2001)</a> created transgenic mice that developed many of the motor symptoms of SBMA and had a truncated, highly expanded AR gene driven by the neurofilament light chain (<a href="/entry/162280">162280</a>) promoter. In addition, transgenic mice created with the prion protein (<a href="/entry/176640">176640</a>) promoter developed widespread neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases. The distribution of neurologic symptoms depended on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or function. The transgenic mice that were generated developed neuronal intranuclear inclusions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. These inclusions were ubiquitinated and sequestered molecular chaperones, components of the 26S proteasome (<a href="/entry/604449">604449</a>) and the transcriptional activator CREB-binding protein (CBP; <a href="/entry/600140">600140</a>). Apart from the presence of NIIs, evidence of neuropathology or neurogenic muscle atrophy was absent, suggesting to the authors that the neurologic phenotypes observed were the result of neuronal dysfunction rather than neuronal degeneration. Similar findings were reported by <a href="#2" class="mim-tip-reference" title="Adachi, H., Kume, A., Li, M., Nakagomi, Y., Niwa, H., Do, J., Sang, C., Kobayashi, Y., Doyu, M., Sobue, G. <strong>Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death.</strong> Hum. Molec. Genet. 10: 1039-1048, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331614</a>] [<a href="https://doi.org/10.1093/hmg/10.10.1039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11331614">Adachi et al. (2001)</a>, who generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human AR promoter. The authors concluded that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11152658+11331614" 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="#113" class="mim-tip-reference" title="McManamny, P., Chy, H. S., Finkelstein, D. I., Craythorn, R. G., Crack, P. J., Kola, I., Cheema, S. S., Horne, M. K., Wreford, N. G., O'Bryan, M. K., de Kretser, D. M., Morrison, J. R. <strong>A mouse model of spinal and bulbar muscular atrophy.</strong> Hum. Molec. Genet. 11: 2103-2111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189162</a>] [<a href="https://doi.org/10.1093/hmg/11.18.2103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189162">McManamny et al. (2002)</a> developed a transgenic model of SBMA expressing a full-length human AR cDNA carrying 65 (AR-65) or 120 CAG repeats (AR-120), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR-120 transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR-120 mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, suggesting that the polyglutamine repeat expansion may cause a dominant gain-of-function mutation in AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189162" 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="#73" class="mim-tip-reference" title="Katsuno, M., Adachi, H., Kume, A., Li, M., Nakagomi, Y., Niwa, H., Sang, C., Kobayashi, Y., Doyu, M., Sobue, G. <strong>Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.</strong> Neuron 35: 843-854, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12372280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12372280</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00834-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12372280">Katsuno et al. (2002)</a> found that the SBMA neurologic phenotype was markedly pronounced in male transgenic mice carrying an AR protein with 97 expanded CAG repeats compared to female mice. The phenotype in males was dramatically rescued by castration, and the few manifestations in the female mice were markedly worsened with testosterone administration. Testosterone in the uncastrated males and treated females was associated with increased translocation of the mutant AR into the nucleus, which was associated with a more severe phenotype. <a href="#73" class="mim-tip-reference" title="Katsuno, M., Adachi, H., Kume, A., Li, M., Nakagomi, Y., Niwa, H., Sang, C., Kobayashi, Y., Doyu, M., Sobue, G. <strong>Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.</strong> Neuron 35: 843-854, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12372280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12372280</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00834-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12372280">Katsuno et al. (2002)</a> concluded that nuclear localization of mutant AR was important in inducing neuronal cell dysfunction and degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12372280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an N-terminal fragment of the human AR protein, <a href="#25" class="mim-tip-reference" title="Chan, H. Y. E., Warrick, J. M., Andriola, I., Merry, D., Bonini, N. M. <strong>Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila.</strong> Hum. Molec. Genet. 11: 2895-2904, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393801</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393801">Chan et al. (2002)</a> studied SBMA in Drosophila. Expression of a pathogenic AR protein with an expanded polyglutamine repeat in Drosophila resulted in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. Flies with a compromised ubiquitin-proteasome pathway showed enhanced degeneration and decreased polyglutamine protein solubility, whereas overexpression of Hsp70 (see <a href="/entry/140550">140550</a>) modulated neurodegeneration. The authors suggested that posttranslational protein modification, including the ubiquitin-proteasome and the UBL1 (<a href="/entry/601912">601912</a>) pathways, may modulate polyglutamine pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393801" 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="#168" class="mim-tip-reference" title="Takeyama, K., Ito, S., Yamamoto, A., Tanimoto, H., Furutani, T., Kanuka, H., Miura, M., Tabata, T., Kato, S. <strong>Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila.</strong> Neuron 35: 855-864, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12372281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12372281</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00875-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12372281">Takeyama et al. (2002)</a> found that Drosophila eye photoreceptor neurons with targeted expression of an expanded AR protein showed increased neurodegeneration following ingestion of either androgen agonists or antagonists. Further protein studies indicated that ligand binding to the mutant expanded protein induced a structural alteration of the AR protein with nuclear translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12372281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study the cellular consequences of chronic low-level exposure to expanded polyglutamine proteins, <a href="#35" class="mim-tip-reference" title="Cowan, K. J., Diamond, M. I., Welch, W. J. <strong>Polyglutamine protein aggregation and toxicity are linked to the cellular stress response.</strong> Hum. Molec. Genet. 12: 1377-1391, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12783846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12783846</a>] [<a href="https://doi.org/10.1093/hmg/ddg151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12783846">Cowan et al. (2003)</a> constructed mouse cell lines expressing either the full-length AR or truncated forms containing 25 or 65 glutamines. Expression of the polyglutamine-expanded truncated AR protein resulted in the formation of cytoplasmic and nuclear aggregates and eventual cell death. Nuclear aggregates preferentially stained positive for hsp72 (HSPA1A; <a href="/entry/140550">140550</a>), a sensitive indicator of a cellular stress response. Biochemical studies revealed that the presence of nuclear aggregates correlated with activation of the c-jun N-terminal kinase (JNK; <a href="/entry/601158">601158</a>). Different metabolic insults, including heat shock treatment, and exposure to sodium arsenite or menadione, proved more toxic to those cells expressing the polyglutamine-expanded truncated protein than to cells expressing the nonexpanded form. Once expressed, hsp72 failed to localize normally and instead was sequestered within the protein aggregates. The authors concluded that abnormal stress responses may contribute to enhanced cell vulnerability in cells expressing polyglutamine-expanded proteins and may increase the propensity of such cells to form cytoplasmic and nuclear inclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12783846" 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="#162" class="mim-tip-reference" title="Sopher, B. L., Thomas, P. S., Jr., LaFevre-Bernt, M. A., Holm, I. E., Wilke, S. A., Ware, C. B., Jin, L.-W., Libby, R. T., Ellerby, L. M., La Spada, A. R. <strong>Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration.</strong> Neuron 41: 687-699, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15003169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15003169</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00082-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15003169">Sopher et al. (2004)</a> found that transgenic mice with a 100-CAG repeat in the AR gene (AR-100) developed a phenotype that was similar to SBMA. Pathologic examination showed AR-positive nuclear inclusions in CNS motor neurons, muscle, and liver, and diffuse AR staining in spinal cord motor neurons. Coimmunoprecipitation studies showed increased binding of Cbp by AR in a glutamine length-dependent fashion, suggesting that polyglutamine tracts may interfere with transcription. <a href="#140" class="mim-tip-reference" title="Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., Van Dorpe, J., Hellings, P., Gorselink, M., Heymans, S., Theilmeier, G., Dewerchin, M., and 20 others. <strong>Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration.</strong> Nature Genet. 28: 131-138, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381259</a>] [<a href="https://doi.org/10.1038/88842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381259">Oosthuyse et al. (2001)</a> reported that deletion of a Cbp-regulated element in the Vegf gene (<a href="/entry/192240">192240</a>) produced an SBMA-like phenotype in mice. Using PCR and protein analysis, <a href="#162" class="mim-tip-reference" title="Sopher, B. L., Thomas, P. S., Jr., LaFevre-Bernt, M. A., Holm, I. E., Wilke, S. A., Ware, C. B., Jin, L.-W., Libby, R. T., Ellerby, L. M., La Spada, A. R. <strong>Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration.</strong> Neuron 41: 687-699, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15003169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15003169</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00082-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15003169">Sopher et al. (2004)</a> found decreased expression of the Vegf164 isoform in AR-100 mice compared to controls. In vitro studies showed that Vegf164 supplementation and overexpression of Cbp independently rescued AR polyglutamine-induced cell death. <a href="#162" class="mim-tip-reference" title="Sopher, B. L., Thomas, P. S., Jr., LaFevre-Bernt, M. A., Holm, I. E., Wilke, S. A., Ware, C. B., Jin, L.-W., Libby, R. T., Ellerby, L. M., La Spada, A. R. <strong>Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration.</strong> Neuron 41: 687-699, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15003169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15003169</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00082-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15003169">Sopher et al. (2004)</a> suggested that SBMA motor neuronopathy involves altered expression of VEGF, consistent with a role for VEGF as a neurotropic/survival factor in motor neuron disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15003169+11381259" 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="#195" class="mim-tip-reference" title="Yu, Z., Dadgar, N., Albertelli, M., Gruis, K., Jordan, C., Robins, D. M., Lieberman, A. P. <strong>Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model.</strong> J. Clin. Invest. 116: 2663-2672, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16981011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16981011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16981011[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/10.1172/JCI28773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16981011">Yu et al. (2006)</a> found that transgenic mice with the 113-CAG repeat (AR113Q) in the AR gene demonstrated androgen-dependent neuromuscular weakness accompanied by myopathic and neuropathic morphologic changes in skeletal muscle, including atrophic, angulated fibers and internal nuclei. AR113Q mice exhibited androgen-dependent early death at 2 to 4 months of age; surgical castration completely prevented early death. Postmortem examination indicated that the mice died of acute urinary tract obstruction due to myopathic changes in the skeletal muscle of the lower urinary tract associated with myotonic discharges. Gene expression analysis of these muscles showed decreased expression of the Clcn1 (<a href="/entry/118425">118425</a>) and Scn4a (<a href="/entry/603967">603967</a>) genes. Hindlimb muscle showed similar myopathic features and decreased expression of Nt4 (<a href="/entry/162662">162662</a>) and Gdnf (<a href="/entry/600837">600837</a>). <a href="#195" class="mim-tip-reference" title="Yu, Z., Dadgar, N., Albertelli, M., Gruis, K., Jordan, C., Robins, D. M., Lieberman, A. P. <strong>Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model.</strong> J. Clin. Invest. 116: 2663-2672, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16981011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16981011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16981011[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/10.1172/JCI28773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16981011">Yu et al. (2006)</a> concluded that there is an important myopathic contribution to the pathogenesis of Kennedy disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16981011" 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="#125" class="mim-tip-reference" title="Monks, D. A., Johansen, J. A., Mo, K., Rao, P., Eagleson, B., Yu, Z., Lieberman, A. P., Breedlove, S. M., Jordan, C. L. <strong>Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease.</strong> Proc. Nat. Acad. Sci. 104: 18259-18264, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984063[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.0705501104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984063">Monks et al. (2007)</a> found that transgenic mice overexpressing wildtype human AR exclusively in skeletal muscle displayed androgen-dependent muscle weakness and early death. Transgenic mice also showed changes in muscle morphology and gene expression consistent with neurogenic atrophy and exhibited motor axon loss. These features reproduced those seen in models of Kennedy disease. <a href="#125" class="mim-tip-reference" title="Monks, D. A., Johansen, J. A., Mo, K., Rao, P., Eagleson, B., Yu, Z., Lieberman, A. P., Breedlove, S. M., Jordan, C. L. <strong>Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease.</strong> Proc. Nat. Acad. Sci. 104: 18259-18264, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984063[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.0705501104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984063">Monks et al. (2007)</a> concluded that toxicity in skeletal muscle is sufficient to cause motoneuron disease and that overexpression of AR can exert toxicity comparable with that of the polyglutamine-expanded protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984063" 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="#127" class="mim-tip-reference" title="Montie, H. L., Cho, M. S., Holder, L., Liu, Y., Tsvetkov, A. S., Finkbeiner, S., Merry, D. E. <strong>Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular dystrophy.</strong> Hum. Molec. Genet. 18: 1937-1950, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19279159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19279159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19279159[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/10.1093/hmg/ddp115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19279159">Montie et al. (2009)</a> genetically manipulated the nuclear localization signal of polyglutamine-expanded AR. Transgenic mice expressing this mutant AR displayed inefficient nuclear translocation and substantially improved motor function compared with Sbma mice. Analysis of cell models of SBMA indicated that nuclear localization of polyglutamine-expanded AR was necessary but not sufficient for aggregation and toxicity and that androgen binding by AR was required for these disease features. Studies of cultured motor neurons showed that the autophagic pathway was able to degrade cytoplasmically retained polyglutamine-expanded AR and represented an endogenous neuroprotective mechanism. Pharmacologic induction of autophagy rescued motor neurons from the toxic effects of even nuclear-residing mutant AR, suggesting a therapeutic role for autophagy in this nucleus-centric disease. <a href="#127" class="mim-tip-reference" title="Montie, H. L., Cho, M. S., Holder, L., Liu, Y., Tsvetkov, A. S., Finkbeiner, S., Merry, D. E. <strong>Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular dystrophy.</strong> Hum. Molec. Genet. 18: 1937-1950, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19279159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19279159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19279159[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/10.1093/hmg/ddp115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19279159">Montie et al. (2009)</a> concluded that polyglutamine-expanded AR must reside within nuclei in the presence of its ligand to cause SBMA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19279159" 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 Drosophila, <a href="#133" class="mim-tip-reference" title="Nedelsky, N. B., Pennuto, M., Smith, R. B., Palazzolo, I., Moore, J., Nie, Z., Neale, G., Taylor, J. P. <strong>Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy.</strong> Neuron 67: 936-952, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20869592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20869592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20869592[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.neuron.2010.08.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20869592">Nedelsky et al. (2010)</a> demonstrated that expression of expanded AR-52Q underwent ligand-dependent nuclear localization in the eye and caused neurodegeneration associated with puncta. Similar systemic neurodegeneration occurred when the mutant gene was expressed in larvae. Studies using mutant constructs lacking certain domains indicated that nuclear translocation of polyQ-expanded AR was necessary, but not sufficient, for toxicity. The protein needed an intact DNA-binding domain for toxicity, suggesting that the normal function of AR as a transcription factor plays a role in pathogenesis. Studies using RNAi-mediated knockdown of downstream AR coregulators and select mutant analysis indicated that a functional AF-2 binding domain was required for toxicity. Importantly, overexpression of wildtype AR showed a similar, yet milder, degenerative phenotype, suggesting that high levels of normal AR activity can cause degeneration even in the absence of polyQ expansion. <a href="#133" class="mim-tip-reference" title="Nedelsky, N. B., Pennuto, M., Smith, R. B., Palazzolo, I., Moore, J., Nie, Z., Neale, G., Taylor, J. P. <strong>Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy.</strong> Neuron 67: 936-952, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20869592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20869592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20869592[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.neuron.2010.08.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20869592">Nedelsky et al. (2010)</a> concluded that SBMA pathogenesis is mediated by amplification of native AR interactions and that polyQ-mediated enhanced AR toxicity requires DNA binding followed by association with AF-2 coregulators. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20869592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Animal Models of Other Diseases</em></strong></p><p>
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In the 'transgenic adenocarcinoma of the mouse prostate' (TRAMP) model, expression of the transgene is initially regulated by androgens and restricted to the prostate epithelial cells of the dorsolateral and ventral lobes (<a href="#45" class="mim-tip-reference" title="Gingrich, J. R., Greenberg, N. M. <strong>A transgenic mouse prostate cancer model.</strong> Toxicol. Path. 24: 502-504, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8864193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8864193</a>] [<a href="https://doi.org/10.1177/019262339602400414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8864193">Gingrich and Greenberg, 1996</a>; <a href="#44" class="mim-tip-reference" title="Gingrich, J. R., Barrios, R. J., Kattan, M. W., Nahm, H. S., Finegold, M. J., Greenberg, N. M. <strong>Androgen-independent prostate cancer progression in the TRAMP model.</strong> Cancer Res. 57: 4687-4691, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9354422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9354422</a>]" pmid="9354422">Gingrich et al., 1997</a>). Spontaneous prostate tumors that histologically resemble the human disease arise with a short latency period and exhibit progression from prostatic intraepithelial neoplasia to severe hyperplasia and adenocarcinoma. <a href="#19" class="mim-tip-reference" title="Buchanan, G., Yang, M., Harris, J. M., Nahm, H. S., Han, G., Moore, N., Bentel, J. M., Matusik, R. J., Horsfall, D. J., Marshall, V. R., Greenberg, N. M., Tilley, W. D. <strong>Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function.</strong> Molec. Endocr. 15: 46-56, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11145738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11145738</a>] [<a href="https://doi.org/10.1210/mend.15.1.0581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11145738">Buchanan et al. (2001)</a> presented the first report of a spontaneous AR gene mutation in the TRAMP mouse and the colocation of this mutation with somatic AR gene mutations identified in human prostate tumors to amino acids 668-671 (QPIF), at the boundary of the hinge and ligand-binding domains. These mutations resulted in AR variants with 2- to 4-fold increased transactivation capacity in response to dihydrotestosterone (DHT) and other nonclassical ligands compared with wildtype AR. Mutations in this region had no apparent effect on receptor levels, ligand-binding kinetics, or DNA binding. The authors concluded that expression of these or similar variants could explain the emergence of hormone-refractory disease in a subset of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9354422+8864193+11145738" 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="#194" class="mim-tip-reference" title="Yeh, S., Tsai, M.-Y., Xu, Q., Mu, X.-M., Lardy, H., Huang, K.-E., Lin, H., Yeh, S.-D., Altuwaijri, S., Zhou, X., Xing, L., Boyce, B. F., Hung, M.-C., Zhang, S., Gan, L., Chang, C. <strong>Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues.</strong> Proc. Nat. Acad. Sci. 99: 13498-13503, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 99: 15245 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12370412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12370412</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12370412[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.212474399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12370412">Yeh et al. (2002)</a> reported the use of a Cre/lox conditional knockout strategy to generate AR knockout mice. Phenotype analysis showed that the AR knockout male mice had a female-like appearance and body weight. Their testes were 80% smaller and serum testosterone concentrations were lower than the wildtype mice. Spermatogenesis was arrested at pachytene spermatocytes. The number and size of adipocytes were also different between the wildtype and AR knockout mice. Cancellous bone volumes of AR knockout male mice were reduced compared with wildtype littermates. The average number of pups per litter in homozygous and heterozygous AR knockout female mice was lower than in wildtype female mice, suggesting potential defects in female fertility and/or ovulation. The model could be useful for studying androgen functions in the selective androgen target tissues in female or male mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12370412" 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="#156" class="mim-tip-reference" title="Sato, T., Matsumoto, T., Yamada, T., Watanabe, T., Kawano, H., Kato, S. <strong>Late onset of obesity in male androgen receptor-deficient (AR KO) mice.</strong> Biochem. Biophys. Res. Commun. 300: 167-171, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12480537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12480537</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)02774-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12480537">Sato et al. (2003)</a> found the male Ar knockout (KO) mice exhibited typical features of testicular feminization in external reproductive organs with growth retardation. The growth curve of male Ar KO mice was similar to that of wildtype female littermates until the tenth week of age, but thereafter mutant males developed obesity. A clear increase in wet weights of white adipose tissues, but not brown adipose tissues, was evident in 30-week-old male Ar KO mice. There was no significant effect of Ar KO on serum lipid parameters or food intake. No accumulation of lipids was found in adipocytes of female homozygous Ar KO mice. <a href="#156" class="mim-tip-reference" title="Sato, T., Matsumoto, T., Yamada, T., Watanabe, T., Kawano, H., Kato, S. <strong>Late onset of obesity in male androgen receptor-deficient (AR KO) mice.</strong> Biochem. Biophys. Res. Commun. 300: 167-171, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12480537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12480537</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)02774-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12480537">Sato et al. (2003)</a> concluded that AR may serve as a negative regulator of adipose development in adult males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12480537" 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="#65" class="mim-tip-reference" title="Ikeda, Y., Aihara, K., Sato, T., Akaike, M., Yoshizumi, M., Suzaki, Y., Izawa, Y., Fujimura, M., Hashizume, S., Kato, M., Yagi, S., Tamaki, T., Kawano, H., Matsumoto, T., Azuma, H., Kato, S., Matsumoto, T. <strong>Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis.</strong> J. Biol. Chem. 280: 29661-29666, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961403</a>] [<a href="https://doi.org/10.1074/jbc.M411694200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961403">Ikeda et al. (2005)</a> found that Ar KO male mice with or without angiotensin II (see <a href="/entry/106150">106150</a>) stimulation showed a significant reduction in heart-to-body weight ratio compared with wildtype male mice. Echocardiographic analysis demonstrated impaired concentric hypertrophic response and left ventricular function in angiotensin II-stimulated Ar KO mice, and Western blot analysis showed that Ar KO mice had reduced angiotensin II-induced Erk signaling (see MAPK3; <a href="/entry/601795">601795</a>). Furthermore, angiotensin II stimulation caused elevated cardiac fibrosis and enhanced expression of fibrosis-related genes in Ar KO mice compared with wildtype mice. <a href="#65" class="mim-tip-reference" title="Ikeda, Y., Aihara, K., Sato, T., Akaike, M., Yoshizumi, M., Suzaki, Y., Izawa, Y., Fujimura, M., Hashizume, S., Kato, M., Yagi, S., Tamaki, T., Kawano, H., Matsumoto, T., Azuma, H., Kato, S., Matsumoto, T. <strong>Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis.</strong> J. Biol. Chem. 280: 29661-29666, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961403</a>] [<a href="https://doi.org/10.1074/jbc.M411694200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961403">Ikeda et al. (2005)</a> concluded that the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during hypertrophic stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961403" 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="#54" class="mim-tip-reference" title="Han, G., Buchanan, G., Ittmann, M., Harris, J. M., Yu, X., DeMayo, F. J., Tilley, W., Greenberg, N. M. <strong>Mutation of the androgen receptor causes oncogenic transformation of the prostate.</strong> Proc. Nat. Acad. Sci. 102: 1151-1156, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15657128[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.0408925102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657128">Han et al. (2005)</a> found that transgenic mice expressing an Ar E231G mutation, corresponding to human E251G, showed rapid development of prostatic intraepithelial neoplasia that progressed to invasive and metastatic cancer. The E231G mutation occurs in a highly conserved signature motif of the N-terminal domain that influences interactions with other cellular coregulators. Significant pathologic changes were not observed in transgenic mice overexpressing wildtype Ar or the T857A mutation, corresponding to human T877A (<a href="#0027">313700.0027</a>). The findings indicated that the E231G mutation induces deregulated growth and that, in some cases, AR may act as an oncogene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15657128" 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="#160" class="mim-tip-reference" title="Shiina, H., Matsumoto, T., Sato, T., Igarashi, K., Miyamoto, J., Takemasa, S., Sakari, M., Takada, I., Nakamura, T., Metzger, D., Chambon, P., Kanno, J., Yoshikawa, H., Kato, S. <strong>Premature ovarian failure in androgen receptor-deficient mice.</strong> Proc. Nat. Acad. Sci. 103: 224-229, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16373508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16373508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16373508[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.0506736102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16373508">Shiina et al. (2006)</a> observed that female Ar-null mice appeared normal but developed premature ovarian failure (see <a href="/entry/311360">311360</a>) with aberrant ovarian gene expression. Eight-week-old Ar -/- females were fertile, but had lower follicle numbers and impaired mammary development, and produced only half of the normal number of pups per litter. Forty-week-old Ar -/- females were infertile due to complete loss of follicles. Genomewide microarray analysis of mRNA from Ar -/- ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by Ar. <a href="#160" class="mim-tip-reference" title="Shiina, H., Matsumoto, T., Sato, T., Igarashi, K., Miyamoto, J., Takemasa, S., Sakari, M., Takada, I., Nakamura, T., Metzger, D., Chambon, P., Kanno, J., Yoshikawa, H., Kato, S. <strong>Premature ovarian failure in androgen receptor-deficient mice.</strong> Proc. Nat. Acad. Sci. 103: 224-229, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16373508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16373508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16373508[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.0506736102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16373508">Shiina et al. (2006)</a> suggested that AR function is required for normal female reproduction, particularly folliculogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16373508" 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>Prostate cancer may become resistant to treatment with androgen deprivation therapy (ADT). <a href="#136" class="mim-tip-reference" title="Niu, Y., Altuwaijri, S., Lai, K.-P., Wu, C.-T., Ricke, W. A., Messing, E. M., Yao, J., Yeh, S., Chang, C. <strong>Androgen receptor is a tumor suppressor and proliferator in prostate cancer.</strong> Proc. Nat. Acad. Sci. 105: 12182-12187, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18723679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18723679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18723679[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.0804700105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18723679">Niu et al. (2008)</a> demonstrated that the prostate AR may function as both a suppressor and a proliferator of prostate cancer metastasis, depending on its tissue location. Coculture of human stromal prostate WPMY1 cells with human AR-null epithelial prostate cancer PC3 cells showed that AR-knockdown in WPMY1 cells or restoration of AR in PC3 cells suppressed prostate cancer metastasis. Furthermore, in bone lesion assays and in vivo mouse models of prostate cancer, restoration of the AR in PC3 epithelial cells resulted in decreased tumor invasion. Knockdown of the AR in epithelial ADT-resistant prostate cancer cells resulted in increased cell invasion in vitro and in vivo. Transgenic mice lacking the prostate epithelial AR showed increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells, which coincided with larger and more invasive metastatic tumors and earlier death compared to wildtype mice. An evaluation of human prostate tumors showed a significant difference in AR expression between primary (91.75%) and metastatic (67.86%) prostate tumors. Together, these results indicated that AR functions in epithelial cells as a tumor suppressor of prostate cancer metastasis, whereas AR acts in stromal cells as a stimulator of prostate cancer progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18723679" 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>60 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=313700[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p><a href="#16" class="mim-tip-reference" title="Brown, T. R., Lubahn, D. B., Wilson, E. M., Joseph, D. R., French, F. S., Migeon, C. J. <strong>Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome: evidence for further genetic heterogeneity in this syndrome.</strong> Proc. Nat. Acad. Sci. 85: 8151-8155, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3186717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3186717</a>] [<a href="https://doi.org/10.1073/pnas.85.21.8151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3186717">Brown et al. (1988)</a> used cDNA probes in the study of patients from 6 unrelated families with complete androgen insensitivity syndrome (<a href="/entry/300068">300068</a>) of the receptor-negative type. The Southern blot pattern was normal in 5 of the 6 patients; in 1 patient a partial deletion of the androgen-receptor gene involving the steroid-binding domain was detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3186717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010477" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010477" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010477</a>
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<p><a href="#145" class="mim-tip-reference" title="Pinsky, L., Trifiro, M., Sebbaghian, N., Kaufman, M., Chang, C., Trapman, J., Brinkmann, A. O., Kuiper, G. G. J. M., Ris, C. J., Brown, C. J., Willard, H. F., Sergovich, F. <strong>A deletional alteration of the androgen receptor (AR) gene in a sporadic patient with complete androgen insensitivity (CAI) who is mentally retarded. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A212, 1989."None>Pinsky et al. (1989)</a> and <a href="#172" class="mim-tip-reference" title="Trifiro, M., Prior, L., Pinsky, L., Kaufman, M., Chang, C., Trapman, J., Brinkmann, A. O., Kuiper, G. G. J. M., Ris, C. <strong>A single transition at an exonic CpG site apparently abolishes androgen receptor (AR)-binding activity in a family with complete androgen insensitivity (CAI). (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A225, 1989."None>Trifiro et al. (1989)</a> reported a patient with complete androgen insensitivity syndrome (<a href="/entry/300068">300068</a>) and a deletion in the AR gene different from that reported by <a href="#16" class="mim-tip-reference" title="Brown, T. R., Lubahn, D. B., Wilson, E. M., Joseph, D. R., French, F. S., Migeon, C. J. <strong>Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome: evidence for further genetic heterogeneity in this syndrome.</strong> Proc. Nat. Acad. Sci. 85: 8151-8155, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3186717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3186717</a>] [<a href="https://doi.org/10.1073/pnas.85.21.8151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3186717">Brown et al. (1988)</a>. The patient also had mental retardation, which may reflect a contiguous gene syndrome; however, no evidence of deletion other than in the AR gene could be obtained by hybridization with 11 additional single-copy probes from Xq11-q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3186717" 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">rs137852562 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852562;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=rs137852562" 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=rs137852562" 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=RCV000010478 OR RCV001056795 OR RCV001818149" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010478, RCV001056795, RCV001818149" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010478...</a>
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<p>In a family with complete androgen insensitivity syndrome (<a href="/entry/300068">300068</a>), <a href="#172" class="mim-tip-reference" title="Trifiro, M., Prior, L., Pinsky, L., Kaufman, M., Chang, C., Trapman, J., Brinkmann, A. O., Kuiper, G. G. J. M., Ris, C. <strong>A single transition at an exonic CpG site apparently abolishes androgen receptor (AR)-binding activity in a family with complete androgen insensitivity (CAI). (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A225, 1989."None>Trifiro et al. (1989)</a> identified a CGC-to-TGC change in exon 6 of the AR gene that resulted in an arg773-to-cys substitution. Position 773 of the androgen receptor is in 1 of 4 regions of its androgen binding domain that are homologous to corresponding regions in the steroid-binding domains of 3 other members of the steroid receptor subfamily that includes those for progesterone, glucocorticoid, and mineralocorticoid.</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> rs137852563 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852563;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/rs137852563?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=rs137852563" 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=rs137852563" 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=RCV000010479" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010479" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010479</a>
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<p>In a case of complete androgen insensitivity (<a href="/entry/300068">300068</a>), <a href="#154" class="mim-tip-reference" title="Sai, T., Seino, S., Chang, C., Trifiro, M., Pinsky, L., Mhatre, A., Kaufman, M., Lambert, B., Trapman, J., Brinkmann, A. O., Rosenfield, R. L., Liao, S. <strong>An exonic point mutation of the androgen receptor gene in a family with complete androgen insensitivity.</strong> Am. J. Hum. Genet. 46: 1095-1100, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2339702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2339702</a>]" pmid="2339702">Sai et al. (1990)</a> demonstrated a guanine-to-adenine transition at nucleotide 2682 of the AR gene, changing codon 717 from tryptophan to a translation stop signal. Codon 717 is in exon 4; thus the mutation predicted synthesis of a truncated receptor that lacked most of its androgen-binding domain. The substitution abolished a recognition sequence for HaeIII. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2339702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852564;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=rs137852564" 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=rs137852564" 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=RCV000010480 OR RCV000763628 OR RCV001381188 OR RCV003421916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010480, RCV000763628, RCV001381188, RCV003421916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010480...</a>
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<p>In a study of sibs with complete androgen insensitivity (<a href="/entry/300068">300068</a>) and reduced AR binding capacity for dihydrotestosterone, <a href="#99" class="mim-tip-reference" title="Lubahn, D. B., Brown, T. R., Simental, J. A., Higgs, H. N., Migeon, C. J., Wilson, E. M., French, F. S. <strong>Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity.</strong> Proc. Nat. Acad. Sci. 86: 9534-9538, 1989. Note: Erratum: Proc. Nat. Acad. Sci. 87: 4411 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594783</a>] [<a href="https://doi.org/10.1073/pnas.86.23.9534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594783">Lubahn et al. (1989)</a> found that the AR steroid-binding domain (exon G) contained a single guanine-to-adenine mutation, resulting in replacement of valine with methionine at amino acid residue 866. As expected, the carrier mother had both normal and mutant AR genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594783" 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> rs137852565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852565;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/rs137852565?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=rs137852565" 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=rs137852565" 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=RCV000010481 OR RCV000698414" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010481, RCV000698414" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010481...</a>
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<p>In 1 of 9 patients with androgen resistance (<a href="/entry/300068">300068</a>) and absent dihydrotestosterone binding in cultured fibroblasts, <a href="#108" class="mim-tip-reference" title="Marcelli, M., Tilley, W. D., Wilson, C. M., Wilson, J. D., Griffin, J. E., McPhaul, M. J. <strong>A single nucleotide substitution introduces a premature termination codon into the androgen receptor gene of a patient with receptor-negative androgen resistance.</strong> J. Clin. Invest. 85: 1522-1528, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2332504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2332504</a>] [<a href="https://doi.org/10.1172/JCI114599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2332504">Marcelli et al. (1990)</a> found a change of tryptophan-794 to a stop codon (TGG to TGA) in the AR gene. S(1) nuclease protection assays showed that normal levels of AR mRNA were present in skin fibroblasts of this patient. Transfection of a mutated androgen receptor cDNA containing a termination codon at position 794 into eukaryotic cells resulted in formation of a normal amount of receptor protein, but the expressed protein did not bind dihydrotestosterone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2332504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852566 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852566;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=rs137852566" 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=rs137852566" 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=RCV000010482" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010482" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010482</a>
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<p>In a patient with complete androgen resistance (<a href="/entry/300068">300068</a>), <a href="#107" class="mim-tip-reference" title="Marcelli, M., Tilley, W. D., Wilson, C. M., Griffin, J. E., Wilson, J. D., McPhaul, M. J. <strong>Definition of the human androgen receptor gene structure permits the identification of mutations that cause androgen resistance: premature termination of the receptor protein at amino acid residue 588 causes complete androgen resistance.</strong> Molec. Endocr. 4: 1105-1116, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2293020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2293020</a>] [<a href="https://doi.org/10.1210/mend-4-8-1105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2293020">Marcelli et al. (1990)</a> found a thymine-for-adenine substitution at nucleotide position 1924 in the AR gene, converting the AAA codon 588 (lysine) into a premature termination codon (TAA). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2293020" 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">rs137852567 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852567;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=rs137852567" 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=rs137852567" 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=RCV000010484" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010484" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010484</a>
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<p><a href="#53" class="mim-tip-reference" title="Grino, P. B., Isidro-Gutierrez, R. F., Griffin, J. E., Wilson, J. D. <strong>Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy.</strong> J. Clin. Endocr. Metab. 68: 578-584, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2918059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2918059</a>] [<a href="https://doi.org/10.1210/jcem-68-3-578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2918059">Grino et al. (1989)</a> described a family in which partial androgen resistance (<a href="/entry/312300">312300</a>) was associated with profound hypospadias but considerable virilization after the time of expected puberty. The androgen receptor expressed in cultured skin fibroblasts from an affected member of this pedigree was normal in amount and exhibited only mild qualitative abnormalities. The functional defect could be largely overcome by high-dose androgen therapy. The clinical features were those of the Reifenstein syndrome. <a href="#115" class="mim-tip-reference" title="McPhaul, M. J., Marcelli, M., Tilley, W. D., Griffin, J. E., Isidro-Gutierrez, R. F., Wilson, J. D. <strong>Molecular basis of androgen resistance in a family with a qualitative abnormality of the androgen receptor and responsive to high-dose androgen therapy.</strong> J. Clin. Invest. 87: 1413-1421, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2010552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2010552</a>] [<a href="https://doi.org/10.1172/JCI115147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2010552">McPhaul et al. (1991)</a> showed that the AR gene in this family contained 2 structural alterations: an A-to-G change at position 2444 in exon 5 that converted tyrosine-761 to cysteine, and a shortened glutamine homopolymeric segment in exon 1 that encoded 12 rather than the usual 20 to 22 glutamines. <a href="#115" class="mim-tip-reference" title="McPhaul, M. J., Marcelli, M., Tilley, W. D., Griffin, J. E., Isidro-Gutierrez, R. F., Wilson, J. D. <strong>Molecular basis of androgen resistance in a family with a qualitative abnormality of the androgen receptor and responsive to high-dose androgen therapy.</strong> J. Clin. Invest. 87: 1413-1421, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2010552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2010552</a>] [<a href="https://doi.org/10.1172/JCI115147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2010552">McPhaul et al. (1991)</a> demonstrated that the presence of the cysteine residue at position 761 caused a rapid dissociation of dihydrotestosterone from the receptor protein. Marked thermolability of the receptor protein was demonstrable only upon introduction of partial deletion of the glutamine homopolymeric segment in addition to the cysteine substitution. The phenotype in this family shows the characteristics referred to as Reifenstein syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2010552+2918059" 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="#129" class="mim-tip-reference" title="Murono, K., Mendonca, B. B., Arnhold, I. J. P., Rigon, A. C. M. M., Migeon, C. J., Brown, T. R. <strong>Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid-binding domain.</strong> Hum. Mutat. 6: 152-162, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581399</a>] [<a href="https://doi.org/10.1002/humu.1380060208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581399">Murono et al. (1995)</a> found this mutation in an individual with androgen sensitivity with ambiguous genitalia; they referred to the mutation as TYR763CYS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581399" 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">rs137852568 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852568;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=rs137852568" 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=rs137852568" 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=RCV000010485" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010485" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010485</a>
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<p>In affected members of a family with complete androgen insensitivity (<a href="/entry/300068">300068</a>), <a href="#173" class="mim-tip-reference" title="Trifiro, M., Prior, R. L., Sabbaghian, N., Pinsky, L., Kaufman, M., Nylen, E. G., Belsham, D. D., Greenberg, C. R., Wrogemann, K. <strong>Amber mutation creates a diagnostic MaeI site in the androgen receptor gene of a family with complete androgen insensitivity.</strong> Am. J. Med. Genet. 40: 493-499, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720929</a>] [<a href="https://doi.org/10.1002/ajmg.1320400425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1720929">Trifiro et al. (1991)</a> found an adenine-to-thymine transversion in exon 8 of the AR gene that changed the sense of codon 882 from lysine to an amber (UAG) translation termination signal. (See <a href="/entry/141900#0312">141900.0312</a> for the origin of the designation 'amber.' See <a href="/entry/219700#0030">219700.0030</a> for an example of the ochre (UAA) type of translation termination signal.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1720929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010478 OR RCV001056795 OR RCV001818149" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010478, RCV001056795, RCV001818149" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010478...</a>
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<p>In a patient with the receptor-negative form of complete testicular feminization (<a href="/entry/300068">300068</a>), <a href="#109" class="mim-tip-reference" title="Marcelli, M., Tilley, W. D., Zoppi, S., Griffin, J. E., Wilson, J. D., McPhaul, M. J. <strong>Androgen resistance associated with a mutation of the androgen receptor at amino acid 772 (arg-to-cys) results from a combination of decreased messenger ribonucleic acid levels and impairment of receptor function.</strong> J. Clin. Endocr. 73: 318-325, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1856263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1856263</a>] [<a href="https://doi.org/10.1210/jcem-73-2-318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1856263">Marcelli et al. (1991)</a> found a single substitution (CGC to TGC) at nucleotide 2476 of the AR gene. This alteration resulted in the conversion of an arginine to a cysteine at amino acid 772. Both a decrease in AR mRNA and impairment of the receptor molecule resulted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1856263" 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">rs137852569 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852569;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=rs137852569" 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=rs137852569" 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=RCV000010487 OR RCV000640478 OR RCV001269612" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010487, RCV000640478, RCV001269612" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010487...</a>
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<p>In 2 unrelated families, <a href="#79" class="mim-tip-reference" title="Klocker, H., Kaspar, F., Eberle, J., Uberreiter, S., Radmayr, C., Bartsch, G. <strong>Point mutation in the DNA binding domain of the androgen receptor in two families with Reifenstein syndrome.</strong> Am. J. Hum. Genet. 50: 1318-1327, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1598912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1598912</a>]" pmid="1598912">Klocker et al. (1992)</a> demonstrated that the Reifenstein syndrome (<a href="/entry/312300">312300</a>) was due to a G-to-A transition at nucleotide 2314 of the AR gene, which changed the alanine codon (GCC) immediately after the first cysteine of the second zinc finger motif of the androgen receptor into a threonine codon (ACC). The 5 patients in the 2 families presented with perineoscrotal hypospadias and undescended testes. After puberty they showed small testes, no palpable prostate, micropenis, azoospermia, and gynecomastia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1598912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852570 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852570;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=rs137852570" 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=rs137852570" 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=RCV000010488" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010488" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010488</a>
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<p>In 2 Japanese sibs with complete androgen insensitivity (<a href="/entry/300068">300068</a>) and undetectable androgen binding in cultured pubic skin fibroblasts, <a href="#130" class="mim-tip-reference" title="Nakao, R., Haji, M., Yanase, T., Ogo, A., Takayanagi, R., Katsube, T., Fukumaki, Y., Nawata, H. <strong>A single amino acid substitution (met786-to-val) in the steroid-binding domain of human androgen receptor leads to complete androgen insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 74: 1152-1157, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1569163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1569163</a>] [<a href="https://doi.org/10.1210/jcem.74.5.1569163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1569163">Nakao et al. (1992)</a> demonstrated a single nucleotide substitution in exon F of the AR gene, resulting in a methionine-to-valine (A-to-G) change at position 786 within the steroid-binding domain of AR. Although reconstruction of this mutation by site-directed mutagenesis into human AR cDNA followed by expression in COS-1 cells led to production of a normal amount and molecular mass of immunodetectable AR protein, the mutant AR showed markedly low affinity of androgen binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1569163" 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> rs137852571 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852571;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/rs137852571?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=rs137852571" 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=rs137852571" 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=RCV000010491 OR RCV002247310 OR RCV003764544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010491, RCV002247310, RCV003764544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010491...</a>
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<p>In 1 of 26 specimens of untreated organ-confined stage B prostate cancer, <a href="#134" class="mim-tip-reference" title="Newmark, J. R., Hardy, D. O., Tonb, D. C., Carter, B. S., Epstein, J. I., Isaacs, W. B., Brown, T. R., Barrack, E. R. <strong>Androgen receptor gene mutations in human prostate cancer.</strong> Proc. Nat. Acad. Sci. 89: 6319-6323, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1631125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1631125</a>] [<a href="https://doi.org/10.1073/pnas.89.14.6319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1631125">Newmark et al. (1992)</a> found a somatic AR mutation by study of genomic DNA by PCR followed by denaturing gradient gel electrophoresis (DGGE); see HPCX3 (<a href="/entry/301120">301120</a>). Sequencing revealed a G-to-A transition in exon E, changing valine to methionine at codon 730. An abundance of the mutated fragment indicated its presence in cells with a growth advantage. The mutation was not detectable in peripheral blood lymphocyte DNA. They postulated that somatic mutation in the AR gene leading to persistent expression could give rise to androgen-independent prostate cancer. Mutation occurred in the hormone-binding domain in a region highly conserved among all steroid receptors. <a href="#134" class="mim-tip-reference" title="Newmark, J. R., Hardy, D. O., Tonb, D. C., Carter, B. S., Epstein, J. I., Isaacs, W. B., Brown, T. R., Barrack, E. R. <strong>Androgen receptor gene mutations in human prostate cancer.</strong> Proc. Nat. Acad. Sci. 89: 6319-6323, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1631125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1631125</a>] [<a href="https://doi.org/10.1073/pnas.89.14.6319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1631125">Newmark et al. (1992)</a> pointed to a possibly comparable situation with an estrogen receptor mRNA variant found in breast cancer that lacked part of the hormone-binding domain; it yielded a mutant receptor that was constitutively active in the absence of estrogen, providing a potential mechanism for estrogen-independent breast cancer growth (<a href="#111" class="mim-tip-reference" title="McGuire, W. L., Chamness, G. C., Fuqua, S. A. W. <strong>Estrogen receptor variants in clinical breast cancer.</strong> Molec. Endocr. 5: 1571-1577, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1779964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1779964</a>] [<a href="https://doi.org/10.1210/mend-5-11-1571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1779964">McGuire et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1631125+1779964" 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>Overexpression of amplified genes is often associated with the acquisition of resistance to cancer therapeutic agents in vitro. <a href="#176" class="mim-tip-reference" title="Visakorpi, T., Hyytinen, E., Koivisto, P., Tanner, M., Keinanen, R., Palmberg, C., Palotie, A., Tammela, T., Isola, J., Kallioniemi, O.-P. <strong>In vivo amplification of the androgen receptor gene and progression of human prostate cancer.</strong> Nature Genet. 9: 401-406, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795646</a>] [<a href="https://doi.org/10.1038/ng0495-401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795646">Visakorpi et al. (1995)</a> identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer that involved amplification of the androgen receptor gene. They found high-level AR amplification in 7 of 23 (30%) recurrent tumors, but in none of the specimens taken from the same patients prior to therapy. Results suggested that AR amplification emerges during androgen deprivation therapy by facilitating tumor cell growth in low androgen concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs3032358 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3032358;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/rs3032358?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=rs3032358" 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=rs3032358" 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=RCV000010492" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010492" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010492</a>
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<p>In 35 unrelated patients with spinal and bulbar muscular atrophy (<a href="/entry/313200">313200</a>), <a href="#87" class="mim-tip-reference" title="La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E., Fischbeck, K. H. <strong>Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.</strong> Nature 352: 77-79, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2062380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2062380</a>] [<a href="https://doi.org/10.1038/352077a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2062380">La Spada et al. (1991)</a> found an increased size of a polymorphic tandem CAG repeat (polyglutamine tract) in the coding region of the androgen receptor gene. These amplified repeats were found in none of 75 controls and segregated with the disease in 15 families. The association was not likely to be due to linkage disequilibrium because 11 different disease alleles were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2062380" 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="#103" class="mim-tip-reference" title="Lund, A., Udd, B., Juvonen, V., Andersen, P. M., Cederquist, K., Davis, M., Gellera, C., Kolmel, C., Ronnevi, L.-O., Sperfeld, A.-D., Sorensen, S.-A., Tranebjaerg, L., Van Maldergem, L., Watanabe, M., Weber, M., Yeung, L., Savontaus, M.-L. <strong>Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.</strong> Europ. J. Hum. Genet. 9: 431-436, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11436124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11436124</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11436124">Lund et al. (2001)</a> haplotyped 123 Kennedy disease families from Finland, Sweden, Norway, Denmark, Germany, Belgium, Italy, Japan, Australia, and Canada. The haplotype analysis showed different founder haplotypes around the world, implying that the CAG repeat expansion mutation in Kennedy disease is not a unique event. No particular expansion-prone haplotype could be detected. Among 95 Kennedy disease patients with defined ages at onset, the authors found a weak negative correlation between the CAG repeat length and the age of onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11436124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, ARG773HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852572 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852572;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=rs137852572" 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=rs137852572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010493 OR RCV001384255 OR RCV001781214" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010493, RCV001384255, RCV001781214" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010493...</a>
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<p>Whereas a C-to-T transition in codon 773 changes arginine to cysteine (<a href="#0003">313700.0003</a>) and results in complete androgen insensitivity (<a href="/entry/300068">300068</a>), a G-to-A transition changes amino acid 773 to histidine and also results in complete androgen insensitivity (<a href="#148" class="mim-tip-reference" title="Prior, L., Bordet, S., Trifiro, M. A., Mhatre, A., Kaufman, M., Pinsky, L., Wrogeman, K., Belsham, D. D., Pereira, F., Greenberg, C., Trapman, J., Brinkman, A. O., Chang, C., Liao, S. <strong>Replacement of arginine 773 by cysteine or histidine in the human androgen receptor causes complete androgen insensitivity with different receptor phenotypes.</strong> Am. J. Hum. Genet. 51: 143-155, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1609793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1609793</a>]" pmid="1609793">Prior et al., 1992</a>). The finding is consistent with the evolutionary preservation of the position homologous to arg773 in the androgen receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1609793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0016 ANDROGEN INSENSITIVITY, PARTIAL, WITH OR WITHOUT BREAST CANCER</strong>
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</h4>
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AR, ARG607GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852573 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852573;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=rs137852573" 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=rs137852573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010494 OR RCV000382955 OR RCV000806067" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010494, RCV000382955, RCV000806067" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010494...</a>
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</span>
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<span class="mim-text-font">
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<p>In brothers with penoscrotal hypospadias who developed infiltrating ductal cancers of the breast at ages 75 and 55 years, respectively, <a href="#191" class="mim-tip-reference" title="Wooster, R., Mangion, J., Eeles, R., Smith, S., Dowsett, M., Averill, D., Barrett-Lee, P., Easton, D. F., Ponder, B. A. J., Stratton, M. R. <strong>A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome.</strong> Nature Genet. 2: 132-134, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303262</a>] [<a href="https://doi.org/10.1038/ng1092-132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303262">Wooster et al. (1992)</a> identified a G-to-A transition in exon 3 of the androgen receptor resulting in an arg607-to-gln (R607Q) substitution. Arg607, which is located within the second zinc finger, is conserved in the androgen, estrogen, glucocorticoid, and mineralocorticoid receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303262" 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="#182" class="mim-tip-reference" title="Weidemann, W., Peters, B., Romalo, G., Spindler, K.-D., Schweikert, H.-U. <strong>Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor.</strong> J. Clin. Endocr. Metab. 83: 1173-1176, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9543136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9543136</a>] [<a href="https://doi.org/10.1210/jcem.83.4.4704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9543136">Weidemann et al. (1998)</a> found the same mutation in an individual with partial androgen insensitivity. At 19 years of age, the patient had undervirilization and endocrine findings typical for androgen insensitivity. In an attempt to improve virilization, high-dose testosterone enanthate treatment (250 mg once a week by intramuscular injection) was begun. After 3.5 years of this treatment, marked promotion of virilization was achieved, i.e., lowering of voice, male pattern secondary hair distribution, marked growth of beard and coarse body hair, increase in phallic size, increase in bone mineral density, and decrease in mammary gland size. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9543136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0017" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0017 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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AR, VAL865MET
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010480 OR RCV000763628 OR RCV001381188 OR RCV003421916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010480, RCV000763628, RCV001381188, RCV003421916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010480...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with complete androgen insensitivity (<a href="/entry/300068">300068</a>), <a href="#76" class="mim-tip-reference" title="Kazemi-Esfarjani, P., Beitel, L. K., Trifiro, M., Kaufman, M., Rennie, P., Sheppard, P., Matusik, R., Pinsky, L. <strong>Substitution of valine-865 by methionine or leucine in the human androgen receptor causes complete or partial androgen insensitivity, respectively with distinct androgen receptor phenotypes.</strong> Molec. Endocr. 7: 37-46, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8446106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8446106</a>] [<a href="https://doi.org/10.1210/mend.7.1.8446106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8446106">Kazemi-Esfarjani et al. (1993)</a> identified a G-to-A transition in exon 7 of the androgen receptor which converted codon 865 from GTG (val) to ATG (met). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8446106" 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>
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<a id="0018" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0018 ANDROGEN INSENSITIVITY, PARTIAL</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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<div style="float: left;">
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AR, VAL865LEU
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852564;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=rs137852564" 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=rs137852564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010496" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010496" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010496</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with partial androgen insensitivity (<a href="/entry/312300">312300</a>), <a href="#76" class="mim-tip-reference" title="Kazemi-Esfarjani, P., Beitel, L. K., Trifiro, M., Kaufman, M., Rennie, P., Sheppard, P., Matusik, R., Pinsky, L. <strong>Substitution of valine-865 by methionine or leucine in the human androgen receptor causes complete or partial androgen insensitivity, respectively with distinct androgen receptor phenotypes.</strong> Molec. Endocr. 7: 37-46, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8446106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8446106</a>] [<a href="https://doi.org/10.1210/mend.7.1.8446106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8446106">Kazemi-Esfarjani et al. (1993)</a> identified a G-to-T transversion in exon 7 of the androgen receptor which converted codon 865 from GTG (val) to TTG (leu). It was remarkable that a methionine substitution of this same codon (<a href="#0017">313700.0017</a>) resulted in complete androgen insensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8446106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0019" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0019 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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AR, ARG855HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs9332971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9332971;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=rs9332971" 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=rs9332971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010497 OR RCV000532628 OR RCV000582251 OR RCV003982834" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010497, RCV000532628, RCV000582251, RCV003982834" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010497...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In 2 Kuwaiti brothers, born to nonconsanguineous parents, who presented in the neonatal period with severe perineal hypospadias, bilateral cryptorchidism, and micropenis, <a href="#5" class="mim-tip-reference" title="Batch, J. A., Evans, B. A. J., Hughes, I. A., Patterson, M. N. <strong>Mutations of the androgen receptor gene identified in perineal hypospadias.</strong> J. Med. Genet. 30: 198-201, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8097257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8097257</a>] [<a href="https://doi.org/10.1136/jmg.30.3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8097257">Batch et al. (1993)</a> found a G-to-A transition in exon G of the AR gene, which caused an arg-to-his substitution at amino acid 855. The 2 boys had 46,XY karyotypes and showed normal testosterone biosynthesis and metabolism. Both showed a qualitative defect in androgen binding (see <a href="/entry/312300">312300</a>), suggesting that the androgen receptor was defective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8097257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0020" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0020 HYPOSPADIAS 1, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div style="float: left;">
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AR, ILE869MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852574 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852574;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=rs137852574" 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=rs137852574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010498" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010498" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010498</a>
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</span>
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<p>In 2 brothers, born to nonconsanguineous parents, who presented at birth with perineal hypospadias (HYSP1; <a href="/entry/300633">300633</a>), <a href="#5" class="mim-tip-reference" title="Batch, J. A., Evans, B. A. J., Hughes, I. A., Patterson, M. N. <strong>Mutations of the androgen receptor gene identified in perineal hypospadias.</strong> J. Med. Genet. 30: 198-201, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8097257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8097257</a>] [<a href="https://doi.org/10.1136/jmg.30.3.198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8097257">Batch et al. (1993)</a> found an A-to-C change in exon 2 of the AR gene, which caused an ile-to-met change at amino acid 869. Both brothers had a 46,XY karyotype, and endocrine investigations were normal in both. Both showed a qualitative defect in androgen binding, suggesting that the androgen receptor was defective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8097257" 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>.0021 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852575 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852575;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=rs137852575" 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=rs137852575" 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=RCV000010499 OR RCV003129750" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010499, RCV003129750" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010499...</a>
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<p>In 2 46,XY sibs with complete testicular feminization (<a href="/entry/300068">300068</a>) and a diminished amount of qualitatively abnormal AR, <a href="#203" class="mim-tip-reference" title="Zoppi, S., Wilson, C. M., Harbison, M. D., Griffin, J. E., Wilson, J. D., McPhaul, M. J., Marcelli, M. <strong>Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation.</strong> J. Clin. Invest. 91: 1105-1112, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8450040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8450040</a>] [<a href="https://doi.org/10.1172/JCI116269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8450040">Zoppi et al. (1993)</a> found a CAG-to-TAG change at nucleotide 340 in exon 1, which caused a gln-to-ter mutation at amino acid 60 in the AR gene. In vitro mutagenesis studies suggested the synthesis of the mutant AR is initiated downstream of the termination codon at reduced levels and that each molecule is functionally impaired. These results defined a novel mechanism causing androgen resistance: the combination of decreased amount and functional impairment of AR caused by an abnormality within the amino terminus of the receptor. <a href="#203" class="mim-tip-reference" title="Zoppi, S., Wilson, C. M., Harbison, M. D., Griffin, J. E., Wilson, J. D., McPhaul, M. J., Marcelli, M. <strong>Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation.</strong> J. Clin. Invest. 91: 1105-1112, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8450040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8450040</a>] [<a href="https://doi.org/10.1172/JCI116269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8450040">Zoppi et al. (1993)</a> determined that the mutation was not present in a 46,XY fetal sib of the proband at 9 weeks' gestation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8450040" 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>.0022 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, 5-KB DEL, EX E
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010500" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010500" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010500</a>
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<p>In a family with complete androgen insensitivity (<a href="/entry/300068">300068</a>), <a href="#105" class="mim-tip-reference" title="MacLean, H. E., Chu, S., Warne, G. L., Zajac, J. D. <strong>Related individuals with different androgen receptor gene deletions.</strong> J. Clin. Invest. 91: 1123-1128, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8450042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8450042</a>] [<a href="https://doi.org/10.1172/JCI116271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8450042">MacLean et al. (1993)</a> found 2 different deletions in the AR gene. Two affected sisters and their heterozygous mother, aunt, and grandmother had a 5-kb deletion of exon E and surrounding introns. An affected (XY) aunt had a 5-kb deletion of exons F and G and surrounding intronic sequences (<a href="#0023">313700.0023</a>). Both deletions had 1 breakpoint in the same 200-bp region of intron 5, but they extended in opposite directions. Both deletions would alter the reading frame of the downstream exons, resulting in the production of abnormal receptors that lack vital parts of the steroid binding domain. The inability of the receptor to bind ligand would thus render the target tissues unresponsive to androgens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8450042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, 5-KB DEL, EX F,G
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010501" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010501" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010501</a>
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<p>See <a href="#0022">313700.0022</a> and <a href="#105" class="mim-tip-reference" title="MacLean, H. E., Chu, S., Warne, G. L., Zajac, J. D. <strong>Related individuals with different androgen receptor gene deletions.</strong> J. Clin. Invest. 91: 1123-1128, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8450042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8450042</a>] [<a href="https://doi.org/10.1172/JCI116271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8450042">MacLean et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8450042" 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>.0024 ANDROGEN INSENSITIVITY, PARTIAL, WITH BREAST CANCER</strong>
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AR, ARG608LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852576;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=rs137852576" 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=rs137852576" 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=RCV000010502" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010502" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010502</a>
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<p>In 1 of 13 cases of male breast cancer, <a href="#97" class="mim-tip-reference" title="Lobaccaro, J.-M., Lumbroso, S., Belon, C., Galtier-Dereure, F., Bringer, J., Lesimple, T., Namer, M., Cutuli, B. F., Pujol, H., Sultan, C. <strong>Androgen receptor gene mutation in male breast cancer.</strong> Hum. Molec. Genet. 2: 1799-1802, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281139</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281139">Lobaccaro et al. (1993)</a> found by single-strand conformation polymorphism and direct sequencing a G-to-A transition at nucleotide 2185 that changed arginine-608 into lysine in a highly conserved region of the second zinc finger of the androgen receptor. The patient was a 38-year-old man with partial androgen insensitivity and normal androgen-binding capacity in cultured genital skin fibroblasts. The authors noted the previously reported arg607-to-gln mutation (<a href="#0016">313700.0016</a>). They concluded that the genetic abnormality was not fortuitous. A decrease in androgen action within breast cells could account for the development of male breast cancer by the loss of a protective effect of androgens on these cells. Activation of estrogen-regulated genes by change in the DNA-binding characteristics of the mutant androgen receptor could not, however, be ruled out. The patient in this case had markedly ambiguous genitalia (micropenis, hypospadias, and bifid scrotum) associated with bilateral gynecomastia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8281139" 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>.0025 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9332969 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9332969;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/rs9332969?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=rs9332969" 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=rs9332969" 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=RCV000010503 OR RCV000582333 OR RCV000814875 OR RCV001269861" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010503, RCV000582333, RCV000814875, RCV001269861" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010503...</a>
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<p><a href="#7" class="mim-tip-reference" title="Beitel, L. K., Kazemi-Esfarjani, P., Kaufman, M., Lumbroso, R., DiGeorge, A. M., Killinger, D. W., Trifiro, M. A., Pinsky, L. <strong>Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance.</strong> J. Clin. Invest. 94: 546-554, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8040309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8040309</a>] [<a href="https://doi.org/10.1172/JCI117368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8040309">Beitel et al. (1994)</a> described an arg839-to-his mutation in affected members of 2 families in whom external genitalia were predominantly female at birth and sex-of-rearing had been female. In a third family, the external genitalia of affected members were predominantly male at birth, and sex-of-rearing had been male; however, these individuals carried an arg839-to-cys mutation (<a href="#0026">313700.0026</a>). In genital skin fibroblasts, both mutant receptors had a normal androgen-binding capacity, but they differed in selected indices of affinity for dihydrotestosterone or 2 synthetic androgens. In transiently cotransfected androgen-treated COS-1 cells, both mutant receptors transactivated a reporter gene subnormally. The his839 mutant was less active than its partner, primarily because its androgen-binding activity was more unstable during prolonged exposure to androgen (see <a href="/entry/312300">312300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8040309" 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>.0026 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852577 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852577;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=rs137852577" 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=rs137852577" 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=RCV000010504 OR RCV000010529 OR RCV000640474 OR RCV001269809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010504, RCV000010529, RCV000640474, RCV001269809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010504...</a>
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<p>See <a href="#0025">313700.0025</a> <a href="#7" class="mim-tip-reference" title="Beitel, L. K., Kazemi-Esfarjani, P., Kaufman, M., Lumbroso, R., DiGeorge, A. M., Killinger, D. W., Trifiro, M. A., Pinsky, L. <strong>Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance.</strong> J. Clin. Invest. 94: 546-554, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8040309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8040309</a>] [<a href="https://doi.org/10.1172/JCI117368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8040309">Beitel et al. (1994)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8040309" 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>.0027 PROSTATE CANCER, SOMATIC</strong>
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AR, THR877ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852578 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852578;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=rs137852578" 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=rs137852578" 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=RCV000010505 OR RCV004668712" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010505, RCV004668712" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010505...</a>
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<p>In 6 of 24 specimens of prostatic tissue derived from transurethral resections in patients with metastatic prostate cancer, <a href="#41" class="mim-tip-reference" title="Gaddipati, J. P., McLeod, D. G., Heidenberg, H. B., Sesterhenn, I. A., Finger, M. J., Moul, J. W., Srivastava, S. <strong>Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.</strong> Cancer Res. 54: 2861-2864, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8187068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8187068</a>]" pmid="8187068">Gaddipati et al. (1994)</a> found a thr877-to-ala mutation in the hormone-binding domain of the AR gene; see HPCX3 (<a href="/entry/301120">301120</a>). The same mutation had been reported previously in a metastatic prostatic cancer cell line where it conferred on the androgen receptor an altered ligand-binding specificity that was stimulated by estrogens, progestagens, and antiandrogens. <a href="#41" class="mim-tip-reference" title="Gaddipati, J. P., McLeod, D. G., Heidenberg, H. B., Sesterhenn, I. A., Finger, M. J., Moul, J. W., Srivastava, S. <strong>Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.</strong> Cancer Res. 54: 2861-2864, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8187068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8187068</a>]" pmid="8187068">Gaddipati et al. (1994)</a> suggested that the codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. The stimulatory effect of the usual therapeutic agents on the codon 877 mutant AR may contribute to treatment-refractory disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8187068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0028 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, LEU676PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852579;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=rs137852579" 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=rs137852579" 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=RCV000010506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010506</a>
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<p>In a large Manitoba Hutterite kindred with X-linked receptor-negative complete androgen insensitivity (<a href="/entry/300068">300068</a>), <a href="#8" class="mim-tip-reference" title="Belsham, D. D., Pereira, F., Greenberg, C. R., Liao, S., Wrogemann, K. <strong>Leu676-to-pro mutation of the androgen receptor causes complete androgen insensitivity syndrome in a large Hutterite kindred.</strong> Hum. Mutat. 5: 28-33, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7537149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7537149</a>] [<a href="https://doi.org/10.1002/humu.1380050104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7537149">Belsham et al. (1995)</a> found a T-to-C transition in exon 4 in the AR gene that resulted in replacement of leucine-676 with proline at a site that is conserved in numerous members of the steroid receptor gene family. The mutation at nucleotide 2558 was found to abolish receptor binding activity when the mutant AR was transfected into COS-1 cells. The mutation was detected by MspI digestion of the PCR-amplified exon 4 product. The propositus and 3 maternal aunts had the complete syndrome. The Manitoba Hutterites are Schmiedeleut and evolved from a relatively small founder population that consisted of a maximum of 124 ancestral genomes (<a href="#92" class="mim-tip-reference" title="Lewis, M., Kaita, H., Giblett, E. R., Anderson, J., Philipps, S., Steinberg, A. G., McAlpine, P. J. <strong>Multiplicity of genetic polymorphisms of blood in the Schmiedeleut Hutterites.</strong> Am. J. Med. Genet. 22: 477-485, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4061484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4061484</a>] [<a href="https://doi.org/10.1002/ajmg.1320220305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4061484">Lewis et al., 1985</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4061484+7537149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0029" class="mim-anchor"></a>
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<strong>.0029 PROSTATE CANCER, SOMATIC</strong>
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AR, THR877SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852580 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852580;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=rs137852580" 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=rs137852580" 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=RCV000010507" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010507" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010507</a>
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<p>Most metastatic androgen-independent prostate cancers express high levels of androgen-receptor gene transcripts. <a href="#169" class="mim-tip-reference" title="Taplin, M.-E., Bubley, G. J., Shuster, T. D., Frantz, M. E., Spooner, A. E., Ogata, G. K., Keer, H. N., Balk, S. P. <strong>Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.</strong> New Eng. J. Med. 332: 1393-1398, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7723794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7723794</a>] [<a href="https://doi.org/10.1056/NEJM199505253322101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7723794">Taplin et al. (1995)</a> identified point mutations in the AR gene in metastatic cells from 5 of 10 patients with prostate cancers in this category (HPCX3; <a href="/entry/301120">301120</a>). One mutation, thr877-to-ser, was in the same codon as that found previously in the androgen-independent prostate cancer cell line (<a href="#0027">313700.0027</a>). In 2 of the 5 patients, the mutations were not detected in the primary tumors. Functional studies of 2 of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen. Four different mutations in the AR gene were identified in 1 tumor (<a href="#0033">313700.0033</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7723794" 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="#190" class="mim-tip-reference" title="Wilson, J. D. <strong>The promiscuous receptor: prostate cancer comes of age. (Editorial)</strong> New Eng. J. Med. 332: 1440-1441, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7723802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7723802</a>] [<a href="https://doi.org/10.1056/NEJM199505253322109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7723802">Wilson (1995)</a> used the expression 'promiscuous receptor' to refer to the mutant receptor that, although losing its specificity for androgen, gains the ability to respond to hormones (estradiol and progesterone) that it would not ordinarily recognize. Under these circumstances, other hormones can play the part ordinarily reserved for androgen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7723802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0030 PROSTATE CANCER, SOMATIC</strong>
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AR, HIS874TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852581 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852581;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=rs137852581" 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=rs137852581" 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=RCV000010508" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010508" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010508</a>
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<p><a href="#169" class="mim-tip-reference" title="Taplin, M.-E., Bubley, G. J., Shuster, T. D., Frantz, M. E., Spooner, A. E., Ogata, G. K., Keer, H. N., Balk, S. P. <strong>Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.</strong> New Eng. J. Med. 332: 1393-1398, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7723794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7723794</a>] [<a href="https://doi.org/10.1056/NEJM199505253322101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7723794">Taplin et al. (1995)</a> found a CAT-to-TAT transition in the AR gene in metastatic cells of prostate cancer in 1 out of 10 patients studied. The nucleotide substitution resulted in a his874-to-tyr amino acid change. See HPCX3 (<a href="/entry/301120">301120</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7723794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0031 PROSTATE CANCER, SOMATIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852582 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852582;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=rs137852582" 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=rs137852582" 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=RCV000010509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010509</a>
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<p><a href="#169" class="mim-tip-reference" title="Taplin, M.-E., Bubley, G. J., Shuster, T. D., Frantz, M. E., Spooner, A. E., Ogata, G. K., Keer, H. N., Balk, S. P. <strong>Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.</strong> New Eng. J. Med. 332: 1393-1398, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7723794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7723794</a>] [<a href="https://doi.org/10.1056/NEJM199505253322101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7723794">Taplin et al. (1995)</a> found a CAA-to-CGA transition in the AR gene in metastatic cells of prostate cancer in 1 out of 10 patients studied. The nucleotide substitution resulted in a gln902-to-arg amino acid change. See HPCX3 (<a href="/entry/301120">301120</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7723794" 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>.0032 PROSTATE CANCER, SOMATIC</strong>
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AR, ALA721THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852583 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852583;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=rs137852583" 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=rs137852583" 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=RCV000010510 OR RCV001305872 OR RCV004767001" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010510, RCV001305872, RCV004767001" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010510...</a>
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<p><a href="#169" class="mim-tip-reference" title="Taplin, M.-E., Bubley, G. J., Shuster, T. D., Frantz, M. E., Spooner, A. E., Ogata, G. K., Keer, H. N., Balk, S. P. <strong>Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.</strong> New Eng. J. Med. 332: 1393-1398, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7723794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7723794</a>] [<a href="https://doi.org/10.1056/NEJM199505253322101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7723794">Taplin et al. (1995)</a> found a GCC-to-ACC transition in the AR gene in metastatic cells of prostate cancer in 1 out of 10 patients studied. The nucleotide substitution led to an ala721-to-thr amino acid change. See HPCX3 (<a href="/entry/301120">301120</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7723794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0033" class="mim-anchor"></a>
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<strong>.0033 PROSTATE CANCER, SOMATIC</strong>
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AR, SER647ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852584 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852584;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=rs137852584" 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=rs137852584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010483" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010483" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010483</a>
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<span class="mim-text-font">
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<p>In a case of metastatic androgen-independent prostate cancer (HPCX3; <a href="/entry/301120">301120</a>), <a href="#169" class="mim-tip-reference" title="Taplin, M.-E., Bubley, G. J., Shuster, T. D., Frantz, M. E., Spooner, A. E., Ogata, G. K., Keer, H. N., Balk, S. P. <strong>Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.</strong> New Eng. J. Med. 332: 1393-1398, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7723794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7723794</a>] [<a href="https://doi.org/10.1056/NEJM199505253322101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7723794">Taplin et al. (1995)</a> found that 100% of metastatic cells carried an AR gene with 4 mutations resulting in the following amino acid substitutions: ser647-to-asn, gly724-to-asp, leu880-to-gln, and ala896-to-thr. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7723794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0034" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0034 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, LEU707ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852585 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852585;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=rs137852585" 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=rs137852585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010511" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010511" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010511</a>
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<span class="mim-text-font">
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<p><a href="#102" class="mim-tip-reference" title="Lumbroso, S., Lobaccaro, J. M., Georget, V., Leger, J., Poujol, N., Terouanne, B., Evain-Brion, D., Czernichow, P., Sultan, C. <strong>A novel substitution (leu707-to-arg) in exon 4 of the androgen receptor gene causes complete androgen resistance.</strong> J. Clin. Endocr. Metab. 81: 1984-1988, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8626869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8626869</a>] [<a href="https://doi.org/10.1210/jcem.81.5.8626869" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8626869">Lumbroso et al. (1996)</a> investigated the molecular basis of androgen resistance in a female newborn with complete testicular feminization (<a href="/entry/300068">300068</a>). Sequencing of the AR gene identified a point mutation in exon 4 responsible for a leucine (CTG)-to-arginine (CGG) replacement at codon 707. This mutation resides in the amino-terminal part of the ligand-binding domain of the AR. In vitro studies showed that the mutant AR was functionally deficient as an androgen-binding molecule. Further, its binding to DNA was reduced and it was unable to induce transcriptional activation of an androgen-responsive reporter gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8626869" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0035" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0035 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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</h4>
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AR, CYS579PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852586 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852586;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=rs137852586" 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=rs137852586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010512" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010512" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010512</a>
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</span>
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<p>In a case of complete androgen insensitivity (<a href="/entry/300068">300068</a>), <a href="#66" class="mim-tip-reference" title="Imasaki, K., Okabe, T., Murakami, H., Tanaka, Y., Haji, M., Takayanagi, R., Nawata, H. <strong>Androgen insensitivity syndrome due to new mutations in the DNA-binding domain of the androgen receptor.</strong> Molec. Cell. Endocr. 120: 15-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8809734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8809734</a>] [<a href="https://doi.org/10.1016/0303-7207(96)03812-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8809734">Imasaki et al. (1996)</a> identified a TGC-to-TTC transversion, changing codon 579 of the AR gene from cys to phe. The mutation occurred in exon B encoding the first zinc finger of the DNA-binding domain of the AR gene. The patient was of the 'receptor-positive type,' i.e., the binding ability of the androgen receptor was normal both quantitatively and qualitatively. The nucleotide and amino acid numeration according to the sequence of <a href="#100" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sar, M., Tan, J., Higgs, H. N., Larson, R. E., French, F. S., Wilson, E. M. <strong>The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate.</strong> Molec. Endocr. 2: 1265-1275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3216866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3216866</a>] [<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3216866">Lubahn et al. (1988)</a> was used to indicate the position of the specific amino acid codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3216866+8809734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0036" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0036 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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</h4>
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</div>
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AR, PHE582TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852587 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852587;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=rs137852587" 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=rs137852587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010513</a>
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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 case of complete androgen insensitivity syndrome (<a href="/entry/300068">300068</a>), <a href="#66" class="mim-tip-reference" title="Imasaki, K., Okabe, T., Murakami, H., Tanaka, Y., Haji, M., Takayanagi, R., Nawata, H. <strong>Androgen insensitivity syndrome due to new mutations in the DNA-binding domain of the androgen receptor.</strong> Molec. Cell. Endocr. 120: 15-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8809734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8809734</a>] [<a href="https://doi.org/10.1016/0303-7207(96)03812-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8809734">Imasaki et al. (1996)</a> identified a TTC-to-TAC transversion in the AR gene, changing codon 582 of the AR gene from phe to tyr. The mutation occurred in exon B encoding the first zinc finger of the DNA-binding domain of the AR gene. The patient was of the 'receptor-positive type,' i.e., the binding ability of the androgen receptor was normal both quantitatively and qualitatively. The nucleotide and amino acid numeration according to the sequence of <a href="#100" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sar, M., Tan, J., Higgs, H. N., Larson, R. E., French, F. S., Wilson, E. M. <strong>The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate.</strong> Molec. Endocr. 2: 1265-1275, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3216866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3216866</a>] [<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3216866">Lubahn et al. (1988)</a> was used to indicate the position of the specific amino acid codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3216866+8809734" 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">rs137852588 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852588;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=rs137852588" 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=rs137852588" 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=RCV000010514 OR RCV004700212" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010514, RCV004700212" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010514...</a>
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<p><a href="#166" class="mim-tip-reference" title="Sutherland, R. W., Wiener, J. S., Hicks, J. P., Marcelli, M., Gonzales, E. T., Roth, D. R., Lamb, D. J. <strong>Androgen receptor gene mutations are rarely associated with isolated penile hypospadias.</strong> J. Urol. 156: 828-831, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8683794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8683794</a>] [<a href="https://doi.org/10.1097/00005392-199608001-00077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8683794">Sutherland et al. (1996)</a> analyzed penile tissue from 40 patients who underwent reconstructive surgery for various degrees of hypospadias and found a C-to-T transition in exon 2 of the androgen receptor gene (pro546 to ser) in only 1 patient. The tissue was analyzed by single-strand conformation polymorphism in exons 2 to 8, followed by DNA sequencing if a possible mutation was found. In the child with the mutation, the distal shaft hypospadias (<a href="/entry/300633">300633</a>) was not associated with other genitourinary anomalies. No other patients had an identifiable mutation in the coding sequences of the exons tested. Of the 26 patients of whom adequate information was obtained, none had an affected father or brother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8683794" 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">rs104894742 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894742;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=rs104894742" 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=rs104894742" 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=RCV000010515" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010515" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010515</a>
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<p>With few exceptions, mutations in the human AR gene associated with androgen insensitivity have been limited to the DNA and steroid binding domains. <a href="#31" class="mim-tip-reference" title="Choong, C. S., Quigley, C. A., French, F. S., Wilson, E. M. <strong>A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation.</strong> J. Clin. Invest. 98: 1423-1431, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8823308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8823308</a>] [<a href="https://doi.org/10.1172/JCI118930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8823308">Choong et al. (1996)</a> characterized the novel molecular mechanism for AIS resulting from a G-to-A transition at codon 2 adjacent to the translation initiation codon in the N-terminal domain of the AR gene in 3 related individuals with partial androgen insensitivity syndrome (<a href="/entry/312300">312300</a>). They stated that this was the first report of a naturally occurring mutation that altered the nucleotide context of the ATG initiation codon at the critical G+4 residue, resulting in reduced translation efficiency. The family pedigree showed 5 affected individuals in 3 generations connected through carrier females in a characteristic X-linked inheritance pattern. The phenotype was that of ambiguous genitalia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8823308" 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>.0039 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852589 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852589;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/rs137852589?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=rs137852589" 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=rs137852589" 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=RCV000010516" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010516" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010516</a>
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<p>In a case of complete androgen insensitivity (<a href="/entry/300068">300068</a>), <a href="#70" class="mim-tip-reference" title="Jakubiczka, S., Nedel, S., Werder, E. A., Schleiermacher, E., Theile, U., Wolff, G., Wieacker, P. <strong>Mutations of the androgen receptor gene in patients with complete androgen insensitivity.</strong> Hum. Mutat. 9: 57-61, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8990010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8990010</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:1<57::AID-HUMU10>3.0.CO;2-O" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8990010">Jakubiczka et al. (1997)</a> identified a met780-to-ile (M780I) missense mutation in the androgen receptor (AR) gene, which resulted from a G-to-T transversion converting ATG to ATT. It is puzzling that <a href="#6" class="mim-tip-reference" title="Batch, J. A., Williams, D. M., Davies, H. R., Brown, B. D., Evans, B. A. J., Hughes, I. A., Patterson, M. N. <strong>Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome.</strong> Hum. Molec. Genet. 1: 497-503, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1307250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1307250</a>] [<a href="https://doi.org/10.1093/hmg/1.7.497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1307250">Batch et al. (1992)</a> described a patient with the same amino acid substitution but the phenotype of partial androgen insensitivity. <a href="#70" class="mim-tip-reference" title="Jakubiczka, S., Nedel, S., Werder, E. A., Schleiermacher, E., Theile, U., Wolff, G., Wieacker, P. <strong>Mutations of the androgen receptor gene in patients with complete androgen insensitivity.</strong> Hum. Mutat. 9: 57-61, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8990010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8990010</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:1<57::AID-HUMU10>3.0.CO;2-O" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8990010">Jakubiczka et al. (1997)</a> suggested that differences in the CAG repeat in exon A may be responsible for the differences in clinical consequences of the M780I mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1307250+8990010" 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>Mutations in the AR gene cause a wide spectrum of androgen insensitivity syndromes. Indeed, patients with the same missense mutation can have strongly divergent phenotypes, suggesting the influence of modifying factors. The polymorphic CAG repeat in the first exon of the AR gene may be such a modifying factor. <a href="#80" class="mim-tip-reference" title="Knoke, I., Allera, A., Wieacker, P. <strong>Significance of the CAG repeat length in the androgen receptor gene (AR) for the transactivation function of an M780I mutant AR.</strong> Hum. Genet. 104: 257-261, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323251</a>] [<a href="https://doi.org/10.1007/s004390050945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323251">Knoke et al. (1999)</a> studied the influence of the length of the CAG repeat on the transactivation function of the M780I mutant AR, which can cause either partial or complete androgen insensitivity syndrome. The studies were done by cotransfection of HeLa cells with various CAG-AR expression vectors and a highly androgen-responsive luciferase reporter gene construct. In contrast to the wildtype AR, the transcriptional activity of the M780I mutant AR could be considerably enhanced by nonphysiologically high androgen concentrations. Furthermore, an inverse relationship between the number of the CAG repeats in the mutant AR and its activity was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323251" 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="#12" class="mim-tip-reference" title="Boehmer, A. L. M., Brinkmann, A. O., Bruggenwirth, H., Van Assendelft, C., Otten, B. J., Verleun-Mooijman, M. C. T., Niermeijer, M. F., Brunner, H. G., Rouwe, C. W., Waelkens, J. J., Oostdijk, W., Kleijer, W. J., Van Der Kwast, T. H., De Vroede, M. A., Drop, S. L. S. <strong>Genotype versus phenotype in families with androgen insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 86: 4151-4160, 2001. Note: Erratum: J. Clin. Endocr. Metab. 87: 3109 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549642</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549642">Boehmer et al. (2001)</a> referred to this mutation as MET771ILE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010497 OR RCV000532628 OR RCV000582251 OR RCV003982834" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010497, RCV000532628, RCV000582251, RCV003982834" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010497...</a>
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<p><a href="#13" class="mim-tip-reference" title="Boehmer, A. L. M., Brinkmann, A. O., Niermeijer, M. F., Bakker, L., Halley, D. J. J., Drop, S. L. S. <strong>Germ-line and somatic mosaicism in the androgen insensitivity syndrome: implications for genetic counseling. (Letter)</strong> Am. J. Hum. Genet. 60: 1003-1006, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106550</a>]" pmid="9106550">Boehmer et al. (1997)</a> described an arg846-to-his (R846H) mutation in the AR gene in 2 sibs with partial androgen insensitivity (<a href="/entry/312300">312300</a>). The mother had one AR allele with 14 CAGs and the other AR allele with 21 CAGs. Both affected brothers had the allele with 14 CAGs. Surprisingly, an unaffected brother also had inherited the AR allele with 14 CAGs, but without the mutation. This segregation pattern indicated that a germline mosaicism was present in the mother. Somatic mosaicism was also demonstrated in the mother; the mother's DNA hybridized with both a normal probe and the R846H probe. The intensity of the hybridization signal of the R846H versus the normal allele suggested that the amount of the mutant R846H allele was less than 10% of the normal allele in peripheral lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9106550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Boehmer, A. L. M., Brinkmann, A. O., Nijman, R. M., Verleun-Mooijman, M. C. T., de Ruiter, P., Niermeijer, M. F., Drop, S. L. S. <strong>Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5-alpha dihydrotestosterone availability.</strong> J. Clin. Endocr. Metab. 86: 1240-1246, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11238515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11238515</a>] [<a href="https://doi.org/10.1210/jcem.86.3.7333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11238515">Boehmer et al. (2001)</a> reported 2 46,XY sibs, children of first-cousin parents, with partial AIS who shared the R846H mutation, but had very different phenotypes. One sib with grade 5 AIS was raised as a girl; the other sib with grade 3 AIS was raised as a boy. In both sibs serum levels of hormones were measured; a sex hormone-binding globulin (SHBG; <a href="/entry/182205">182205</a>) suppression test was completed; and mutation analysis of the AR gene, Scatchard, and SDS-PAGE analysis of the AR protein was performed. Furthermore, steroid 5-alpha-reductase-2 (SRD5A2; <a href="/entry/607306">607306</a>) expression and activity in genital skin fibroblasts were investigated, and the SRD5A2 gene was sequenced. The decrease in SHBG serum levels in an SHBG suppression test did not suggest differences in androgen sensitivity as the cause of the phenotypic variation. Also, androgen binding characteristics of the AR, AR expression levels, and the phosphorylation pattern of the AR on hormone binding were identical in both sibs. However, SRD5A2 activity was normal in genital skin fibroblasts from the phenotypic male patient but undetectable in genital skin fibroblasts from the phenotypic female patient. The lack of SRD5A2 activity was due to absent or reduced expression of SRD5A2 in genital skin fibroblasts from the phenotypic female patient. Exon and flanking intron sequences of the SRD5A2 gene showed no mutations in either sib. Therefore, the absent or reduced expression of SRD5A2 is likely to be additional to the AIS. The authors concluded that (1) distinct phenotypic variation in this family was caused by SRD5A2 deficiency, additional to AIS; (2) this 5-alpha-reductase deficiency was due to absence of expression of SRD5A2 as shown by molecular studies, and (3) the distinct phenotypic variation in AIS here is explained by differences in the availability of 5-alpha-dihydrotestosterone during embryonic sex differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11238515" 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">rs2147497386 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147497386;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=rs2147497386" 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=rs2147497386" 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=RCV000010518" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010518" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010518</a>
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<p><a href="#17" class="mim-tip-reference" title="Bruggenwirth, H. T., Boehmer, A. L. M., Ramnarain, S., Verleun-Mooijman, M. C. T., Satijn, D. P. E., Trapman, J., Grootegoed, J. A., Brinkmann, A. O. <strong>Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation.</strong> Am. J. Hum. Genet. 61: 1067-1077, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345099</a>] [<a href="https://doi.org/10.1086/301605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9345099">Bruggenwirth et al. (1997)</a> found an unusual intronic mutation in a family in which 2 brothers and a maternal uncle had partial androgen insensitivity syndrome (<a href="/entry/312300">312300</a>). All affected individuals were 46,XY and had a female habitus with normal female external genitalia, and normal but underdeveloped testes with epididymides and vasa deferentia present. No mullerian remnants were found. In the coding part and the intron/exon boundaries of the AR gene, no mutation was found. The androgen receptor displayed normal ligand-binding parameters and migrated as a 110- to 112-kD doublet on SDS-PAGE in the absence of hormone. However, after culturing of the patient's genital skin fibroblasts in the presence of hormone, the slower-migrating 114-kD protein, which reflects hormone-dependent phosphorylation, was hardly detectable. Furthermore, receptor protein was undetectable in the nuclear fraction of fibroblasts after treatment with hormone, which is indicative of defective DNA binding. Sequencing of the AR gene revealed a T-to-A transversion 11-bp upstream of exon 3 in intron 2. Analysis of mRNA revealed that splicing involved a cryptic splice site, located 71/70-bp upstream of exon 3, resulting in generation of mRNA with an insert of 69 nucleotides. In addition, a small amount of a transcript with a deleted exon 3 and a very low level of wildtype transcript were detected. Translation of the extended transcript resulted in an androgen receptor protein with 23 amino acid residues inserted between the 2 zinc clusters, displaying defective DNA binding and defective transcription activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9345099" 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">rs137852590 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852590;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=rs137852590" 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=rs137852590" 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=RCV000010519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010519</a>
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<p>In an adult patient with a 46,XY karyotype presenting with signs of partial virilization (see <a href="/entry/312300">312300</a>) (pubic hair Tanner stage 4 and clitoral enlargement), <a href="#60" class="mim-tip-reference" title="Holterhus, P.-M., Bruggenwirth, H. T., Hiort, O., Kleinkauf-Houcken, A., Kruse, K., Sinnecker, G. H. G., Brinkmann, A. O. <strong>Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 82: 3584-3589, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9360511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9360511</a>] [<a href="https://doi.org/10.1210/jcem.82.11.4375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9360511">Holterhus et al. (1997)</a> identified a premature stop codon in exon 1 of the AR gene. A T-to-G transversion in codon 172 of the AR gene was detected that replaced the original TTA (leu) with a premature TGA stop codon. No other family members were affected. Examination of the sequencing gel identified a wildtype allele, indicating a mosaicism. In addition, elimination of the unique AftII recognition site induced by the mutation was incomplete, thus confirming mosaicism. Normal androgen binding studies demonstrated expression of the wildtype AR in the patient's genital skin fibroblasts. Premature stop codons of the AR gene are usually associated with a complete androgen insensitivity syndrome. <a href="#60" class="mim-tip-reference" title="Holterhus, P.-M., Bruggenwirth, H. T., Hiort, O., Kleinkauf-Houcken, A., Kruse, K., Sinnecker, G. H. G., Brinkmann, A. O. <strong>Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 82: 3584-3589, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9360511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9360511</a>] [<a href="https://doi.org/10.1210/jcem.82.11.4375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9360511">Holterhus et al. (1997)</a> concluded that somatic mosaicism of the AR gene shifts the phenotype to a higher degree of virilization than expected from the genotype of the mutant allele alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9360511" 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>.0043 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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AR, GLN798GLU
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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> rs137852591 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852591;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/rs137852591?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=rs137852591" 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=rs137852591" 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=RCV000010520 OR RCV000224621 OR RCV001519068 OR RCV002247311 OR RCV003234899 OR RCV003982835" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010520, RCV000224621, RCV001519068, RCV002247311, RCV003234899, RCV003982835" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010520...</a>
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<p><a href="#181" class="mim-tip-reference" title="Wang, Q., Ghadessy, F. J., Trounson, A., de Kretser, D., McLachlan, R., Ng, S. C., Yong, E. L. <strong>Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation.</strong> J. Clin. Endocr. Metab. 83: 4303-4309, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851768</a>] [<a href="https://doi.org/10.1210/jcem.83.12.5358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9851768">Wang et al. (1998)</a> screened 234 subjects with defective spermatogenesis and identified an azoospermic subject with a gln798-to-glu (Q798E) substitution of the AR gene product. This germline mutation was not detected in 110 fertile controls, was associated with features of minimal androgen insensitivity in the subject (see <a href="/entry/312300">312300</a>), had been related to more severe grades of AR (<a href="#9" class="mim-tip-reference" title="Bevan, C. L., Brown, B. B., Davies, H. R., Evans, B. A. J., Hughes, I. A., Patterson, M. N. <strong>Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome.</strong> Hum. Molec. Genet. 5: 265-273, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824883</a>] [<a href="https://doi.org/10.1093/hmg/5.2.265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8824883">Bevan et al., 1996</a>), and caused a subtle, but significant, decrease in receptor trans-activation function in vitro that was consistent with the phenotype. Despite being in the middle of the ligand-binding domain of the AR, the Q798E mutation did not cause any ligand-binding defect, indicating that this highly conserved residue has a trans-activation function but does not directly form part of the ligand-binding pocket. The transactivation defect of the mutant receptor can be rectified in vitro with the androgenic drug fluoxymesterone, but not with mesterolone or nortestosterone. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9851768+8824883" 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>.0044 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852592 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852592;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=rs137852592" 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=rs137852592" 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=RCV000010521 OR RCV003133116" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010521, RCV003133116" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010521...</a>
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<p><a href="#139" class="mim-tip-reference" title="Ong, Y. C., Wong, H. B., Adaikan, G., Yong, E. L. <strong>Directed pharmacological therapy of ambiguous genitalia due to an androgen receptor gene mutation. (Letter)</strong> Lancet 354: 1444-1445, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10543676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10543676</a>] [<a href="https://doi.org/10.1016/s0140-6736(99)03205-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10543676">Ong et al. (1999)</a> identified a met807-to-thr mutation in the AR gene in a 46,XY infant with partial androgen insensitivity (<a href="/entry/312300">312300</a>). Treatment with a dihydrotestosterone gel, applied topically to the periscrotal region 3 times a day, for 5 weeks resulted in improved male genital development. The authors stated that in vitro functional assays can help identify the subset of patients with ambiguous genitalia who could respond well to androgen therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10543676" 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>.0045 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs759327087 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759327087;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/rs759327087?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=rs759327087" 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=rs759327087" 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=RCV000010522" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010522" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010522</a>
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<p>In a large kindred with complete androgen insensitivity syndrome (<a href="/entry/300068">300068</a>), <a href="#198" class="mim-tip-reference" title="Zhu, Y.-S., Cai, L.-Q., Cordero, J. J., Canovatchel, W. J., Katz, M. D., Imperato-McGinley, J. <strong>A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred.</strong> J. Clin. Endocr. Metab. 84: 1590-1594, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323385</a>] [<a href="https://doi.org/10.1210/jcem.84.5.5695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323385">Zhu et al. (1999)</a> identified a mutation in the polymorphic CAG trinucleotide region of exon 1 of the AR gene, where a single A is inserted at nucleotide 179, or equivalently, a GC dinucleotide is deleted at nucleotide 180 (<a href="#0046">313700.0046</a>). Both mutations result in a frameshift at amino acid 60 and a premature termination of the receptor downstream of the mutation, predicting a mutant AR with only 79 amino acids in the N terminus, which prohibits binding to the ligand as well as the cognate DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323385" 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>.0046 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, 2-BP DEL, 180GC
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869320731 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320731;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=rs869320731" 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=rs869320731" 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=RCV000010489" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010489" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010489</a>
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<p>See <a href="#0045">313700.0045</a> and <a href="#198" class="mim-tip-reference" title="Zhu, Y.-S., Cai, L.-Q., Cordero, J. J., Canovatchel, W. J., Katz, M. D., Imperato-McGinley, J. <strong>A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred.</strong> J. Clin. Endocr. Metab. 84: 1590-1594, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323385</a>] [<a href="https://doi.org/10.1210/jcem.84.5.5695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323385">Zhu et al. (1999)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323385" 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>.0047 PROSTATE CANCER SUSCEPTIBILITY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852593 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852593;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/rs137852593?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=rs137852593" 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=rs137852593" 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=RCV000010523 OR RCV002247312 OR RCV003764545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010523, RCV002247312, RCV003764545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010523...</a>
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<p><a href="#39" class="mim-tip-reference" title="Elo, J. P., Kvist, L., Leinonen, K., Isomaa, V., Hentuu, P., Lukkarinen, O., Vihko, P. <strong>Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol.</strong> J. Clin. Endocr. Metab. 80: 3494-3500, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8530589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8530589</a>] [<a href="https://doi.org/10.1210/jcem.80.12.8530589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8530589">Elo et al. (1995)</a> described a germline G-T transversion in exon E of the AR gene, resulting in an arg726-to-leu (R726L) substitution, in a patient with prostate cancer (HPCX3; <a href="/entry/301120">301120</a>) from northern Finland. <a href="#83" class="mim-tip-reference" title="Koivisto, P. A., Schleutker, J., Helin, H., Ehren-van Eekelen, C., Kallioniemi, O.-P., Trapman, J. <strong>Androgen receptor gene alterations and chromosomal gains and losses in prostate carcinomas appearing during finasteride treatment for benign prostatic hyperplasia.</strong> Clin. Cancer Res. 5: 3578-3582, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10589774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10589774</a>]" pmid="10589774">Koivisto et al. (1999)</a> found the same mutation in another Finnish prostate cancer patient when screening for AR mutations by single-strand conformation polymorphism in 6 patients whose cancers appeared during finasteride treatment for benign prostatic hyperplasia. The R726L mutation affected the hormone-binding region in exon E and led to activation of the androgen receptor not only by dihydrotestosterone and testosterone but also by estradiol. The fact that this mutation had not been found in any published studies of the AR gene suggested that it might represent a unique Finnish mutation. <a href="#126" class="mim-tip-reference" title="Mononen, N., Syrjakoski, K., Matikainen, M., Tammela, T. L. J., Schleutker, J., Kallioniemi, O.-P., Trapman, J., Koivisto, P. A. <strong>Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene.</strong> Cancer Res. 60: 6479-6481, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11103816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11103816</a>]" pmid="11103816">Mononen et al. (2000)</a> analyzed the frequency of the R726L mutation in over 1,400 specimens from blood donors, 418 consecutive prostate cancer patients with no family history of prostate cancer, and 106 patients with a positive family history of prostate cancer. Its frequency in blood donors was 3 in 900 (0.33%). In contrast, 8 (1.91%) were mutations found in the prostate cancer group without family history, and 2 (1.89%) were mutations found in the hereditary group. <a href="#126" class="mim-tip-reference" title="Mononen, N., Syrjakoski, K., Matikainen, M., Tammela, T. L. J., Schleutker, J., Kallioniemi, O.-P., Trapman, J., Koivisto, P. A. <strong>Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene.</strong> Cancer Res. 60: 6479-6481, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11103816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11103816</a>]" pmid="11103816">Mononen et al. (2000)</a> suggested that the R726L substitution in the AR gene may confer up to 6-fold increased risk of prostate cancer and may contribute to cancer development in up to 2% of Finnish prostate cancer patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10589774+8530589+11103816" 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>.0048 ANDROGEN INSENSITIVITY SYNDROME</strong>
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AR, SER888SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852594 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852594;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=rs137852594" 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=rs137852594" 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=RCV000010524 OR RCV001059742 OR RCV001785450" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010524, RCV001059742, RCV001785450" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010524...</a>
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<p>In a patient with partial androgen sensitivity syndrome (<a href="/entry/300068">300068</a>), <a href="#56" class="mim-tip-reference" title="Hellwinkel, O. J.-C., Holterhus, P.-M., Struve, D., Marschke, C., Homburg, N., Hiort, O. <strong>A unique exonic splicing mutation in the human androgen receptor gene indicates a physiologic relevance of regular androgen receptor transcript variants.</strong> J. Clin. Endocr. Metab. 86: 2569-2575, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11397856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11397856</a>] [<a href="https://doi.org/10.1210/jcem.86.6.7543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11397856">Hellwinkel et al. (2001)</a> identified a single, presumably silent nucleotide variation (AGC to AGT) at codon 888 in exon 8 of the AR gene. However, in the patient's genital skin fibroblasts, a truncated transcript of 5.5 kb (normal: 10.5 kb) was detected, which lacked a part of exon 8 and much of the 3-prime untranslated region. The translation product includes 8 missense amino acids from codon 886 onward followed by a premature stop codon. The mutant protein was shown by in vitro expression analysis to lack any residual function. However, RT-PCR products included 2 additional splicing variants of 6.4 and 7.8 kb in both patient and normal control genital skin fibroblasts. These splicing variants comprise the complete coding region but a shortened 3-prime untranslated region. Thus, a distinct alternative pre-mRNA processing event leading to 2 additional transcripts occurs generally in genital skin fibroblasts. In addition, this process partially prevents aberrant splicing in the patient and produces a small fraction of normal, functional intact AR protein that could explain the partial masculinization in this patient. The authors concluded that an exonic splicing mutation in the AR gene indicates a physiologic relevance of the regular AR mRNA variants with shortened 3-prime untranslated regions and their functional translation products in human genital development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11397856" 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>.0049 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1602278831 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1602278831;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=rs1602278831" 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=rs1602278831" 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=RCV000010525" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010525" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010525</a>
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<p><a href="#155" class="mim-tip-reference" title="Sammarco, I., Grimaldi, P., Rossi, P., Cappa, M., Moretti, C., Frajese, G., Geremia, R. <strong>Novel point mutation in the splice donor site of exon-intron junction 6 of the androgen receptor gene in a patient with partial androgen insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 85: 3256-3261, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10999818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10999818</a>] [<a href="https://doi.org/10.1210/jcem.85.9.6815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10999818">Sammarco et al. (2000)</a> reported an 11-year-old XY girl, with clinical manifestations of impaired androgen biologic action (<a href="/entry/312300">312300</a>), including female phenotype, blind-ending vagina, small degree of posterior labial fusion, and absence of uterus, fallopian tubes, and ovaries. At diagnosis the patient had a FSH/LH ratio according to the pubertal stage, undetectable 17-beta-estradiol, and high levels of testosterone (80.1 ng/mL). After bilateral gonadectomy, performed at the age of 11 years, histologic examination showed small embryonic seminiferous tubules containing prevalently Sertoli cells and occasional spermatogonia together with abundant fibrous tissue. Molecular study of the patient showed a G-to-T transversion in position +5 of the donor splice site in the junction between exon 6 and intron 6 of the AR gene. Analysis of RT-PCR products from AR mRNA from cultured genital skin fibroblasts of the patient suggested that splicing was defective, and intron 6 was retained in most of the receptor mRNA molecules. Immunoblotting showed that most of the expressed protein lacked part of the C-terminal hormone-binding domain, and a small amount of normal receptor was observed. The authors concluded that this was probably responsible for the reduced binding capacity in genital skin fibroblasts of the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10999818" 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>.0050 ANDROGEN INSENSITIVITY SYNDROME</strong>
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AR, LEU712PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852595 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852595;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=rs137852595" 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=rs137852595" 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=RCV000010526" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010526" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010526</a>
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<p><a href="#61" class="mim-tip-reference" title="Holterhus, P.-M., Sinnecker, G. H. G., Hiort, O. <strong>Phenotypic diversity and testosterone-induced normalization of mutant L712F androgen receptor function in a kindred with androgen insensitivity.</strong> J. Clin. Endocr. Metab. 85: 3245-3250, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10999816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10999816</a>] [<a href="https://doi.org/10.1210/jcem.85.9.6812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10999816">Holterhus et al. (2000)</a> reported a family with 4 individuals with androgen insensitivity syndrome (<a href="/entry/300068">300068</a>), 3 brothers (B1-B3) and their uncle, displaying strikingly different external genitalia: B1, ambiguous; B2, severe micropenis; B3, slight micropenis; and uncle, micropenis and penoscrotal hypospadias. All had been assigned a male gender. <a href="#61" class="mim-tip-reference" title="Holterhus, P.-M., Sinnecker, G. H. G., Hiort, O. <strong>Phenotypic diversity and testosterone-induced normalization of mutant L712F androgen receptor function in a kindred with androgen insensitivity.</strong> J. Clin. Endocr. Metab. 85: 3245-3250, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10999816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10999816</a>] [<a href="https://doi.org/10.1210/jcem.85.9.6812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10999816">Holterhus et al. (2000)</a> detected the same leu712-to-phe (CTT-TTT, L712F) AR mutation in each subject. Methyltrienolone binding on cultured genital skin fibroblasts of B2 suggested moderate impairment of the ligand-binding domain. In trans-activation assays, the 712F mutant showed considerable deficiency at low concentrations of testosterone (0.01-0.1 nmol/L) or dihydrotestosterone (0.01 nmol/L). Remarkably, this deficiency could be fully neutralized by testosterone concentrations greater than 1.0 nmol/L. Hence, the 712F AR could switch its function from subnormal to normal within the physiologic concentration range of testosterone. This was reflected by an excellent response to testosterone therapy in B1, B2, and the uncle. The authors concluded that, taking into account the well documented individual and time-dependent variation in testosterone concentration in early fetal development, their observations illustrated the potential impact of varying ligand concentrations for distinct cases of phenotypic variability in AIS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10999816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0051 ANDROGEN INSENSITIVITY SYNDROME</strong>
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AR, GLY577ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852596 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852596;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=rs137852596" 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=rs137852596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010527" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010527" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010527</a>
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<p><a href="#135" class="mim-tip-reference" title="Nguyen, D., Steinberg, S. V., Rouault, E., Chagnon, S., Gottlieb, B., Pinsky, L., Trifiro, M., Mader, S. <strong>A G577R mutation in the human AR P box results in selective decreases in DNA binding and in partial androgen insensitivity syndrome.</strong> Molec. Endocr. 15: 1790-1802, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11579211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11579211</a>] [<a href="https://doi.org/10.1210/mend.15.10.0709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11579211">Nguyen et al. (2001)</a> characterized a novel mutation of the human androgen receptor (AR), gly577 to arg (G577R), associated with partial androgen insensitivity syndrome (<a href="/entry/300068">300068</a>). G577 is the first amino acid of the P box, a region crucial for the selectivity of receptor/DNA interaction. Although the equivalent amino acid in the glucocorticoid receptor (GR; <a href="/entry/138040">138040</a>), also gly, is not involved in DNA interaction, the residue at the same position in the estrogen receptor (ER; <a href="/entry/133430">133430</a>), glu, interacts with the 2 central base pairs in the PuGGTCA motif. The authors observed that the G577R mutation does not induce binding to probes that are not recognized by the wildtype AR. However, binding to the 4 PuGNACA elements recognized by the wildtype AR was affected to different degrees, resulting in an altered selectivity of DNA response element recognition. In particular, the G577R mutant did not interact with PuGGACA palindromes. Modeling of the complex between mutant AR and PuGNACA motifs indicates that the destabilizing effect of the mutation is attributable to a steric clash between the C-beta of arg at position 1 of the P box and the methyl group of the second thymine residue in the TGTTCPy arm of the palindrome. The authors concluded that androgen target genes may be differentially affected by the G577R mutation. They stated that G577R was the first natural mutation characterized that alters the selectivity of the AR/DNA interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11579211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0052" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0052 ANDROGEN INSENSITIVITY SYNDROME</strong>
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AR, SER865PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852597 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852597;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=rs137852597" 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=rs137852597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010528" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010528" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010528</a>
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<p><a href="#124" class="mim-tip-reference" title="Mongan, N. P., Jaaskelainen, J., Green, K., Schwabe, J. W., Shimura, N., Dattani, M., Hughes, I. A. <strong>Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins.</strong> J. Clin. Endocr. Metab. 87: 1057-1061, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889162</a>] [<a href="https://doi.org/10.1210/jcem.87.3.8329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889162">Mongan et al. (2002)</a> reported monozygotic twins diagnosed with complete androgen insensitivity syndrome (AIS; <a href="/entry/300068">300068</a>) who each possessed 2 substitutions in the AR gene (C to G at position 2930 and T to C at position 2955, both in exon 7), leading to phe856-to-leu (F856L; <a href="#0053">313700.0053</a>) and ser865-to-pro (S865P) mutations, respectively. Neither parent was found to be a carrier for these mutations, indicating that the double mutation arose de novo. Both mutations were recreated by site-directed mutagenesis and compared functionally with the wildtype receptor. The F856L mutation did not affect androgen binding when expressed in COS-1 cells, nor did it decrease androgen-dependent transactivation in transfected HeLa cells. However, the S865P mutation completely ablated androgen binding and transactivation. The authors concluded that replacement of serine by proline at position 865 was sufficient to cause complete AIS in these twins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11889162" 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>.0053 ANDROGEN INSENSITIVITY SYNDROME</strong>
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AR, PHE856LEU
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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> rs137852598 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852598;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/rs137852598?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=rs137852598" 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=rs137852598" 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=RCV000010490" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010490" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010490</a>
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<p>See <a href="#0052">313700.0052</a> and <a href="#124" class="mim-tip-reference" title="Mongan, N. P., Jaaskelainen, J., Green, K., Schwabe, J. W., Shimura, N., Dattani, M., Hughes, I. A. <strong>Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins.</strong> J. Clin. Endocr. Metab. 87: 1057-1061, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889162</a>] [<a href="https://doi.org/10.1210/jcem.87.3.8329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889162">Mongan et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11889162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0054" class="mim-anchor"></a>
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<strong>.0054 ANDROGEN INSENSITIVITY SYNDROME</strong>
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AR, ARG840CYS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010504 OR RCV000010529 OR RCV000640474 OR RCV001269809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010504, RCV000010529, RCV000640474, RCV001269809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010504...</a>
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<p><a href="#32" class="mim-tip-reference" title="Chu, J., Zhang, R., Zhao, Z., Zou, W., Han, Y., Qi, Q., Zhang, H., Wang, J.-C., Tao, S., Liu, X., Luo, Z. <strong>Male fertility is compatible with an Arg840Cys substitution in the AR in a large Chinese family with divergent phenotypes of AR insensitivity syndrome.</strong> J. Clin. Endocr. Metab. 87: 347-351, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788673</a>] [<a href="https://doi.org/10.1210/jcem.87.1.8167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11788673">Chu et al. (2002)</a> reported an arg840-to-cys (R840C) substitution in the AR gene in a large Chinese pedigree with AIS (<a href="/entry/300068">300068</a>). The mutant gene may result in infertility for some affected males with or without hypospadias. However, it was also observed that the mutation did not affect the fertility of the other patients. The gonadotropin levels for 1 of these patients were within normal range. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11788673" 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>.0055 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852599 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852599;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=rs137852599" 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=rs137852599" 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=RCV000010530" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010530" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010530</a>
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<p><a href="#153" class="mim-tip-reference" title="Rosa, S., Biason-Lauber, A., Mongan, N. P., Navratil, F., Schoenle, E. J. <strong>Complete androgen insensitivity syndrome caused by a novel mutation in the ligand-binding domain of the androgen receptor: functional characterization.</strong> J. Clin. Endocr. Metab. 87: 4378-4382, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213902</a>] [<a href="https://doi.org/10.1210/jc.2002-020139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213902">Rosa et al. (2002)</a> described a 46,XY phenotypically female patient with all of the characteristics of complete androgen sensitivity (<a href="/entry/300068">300068</a>), i.e., primary amenorrhea, no axillary or pubic hair, female external genitalia, no uterus, and undescended testes. An A-to-C transition in exon 4 of the AR gene led to a novel missense his689-to-pro (H689P) mutation in the ligand-binding domain of the AR protein. Functional studies demonstrated that the mutated AR is unable to efficiently bind its natural ligand dihydrotestosterone and to trans-activate androgen response elements. The authors concluded that their analysis of the structural consequences of the H689P substitution suggests that this mutation is likely to perturb the conformation of the second helix of the AR ligand-binding domain, which contains residues critical for androgen binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213902" 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>.0056 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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ANDROGEN INSENSITIVITY, COMPLETE, INCLUDED
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AR, GLY743VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852600 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852600;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=rs137852600" 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=rs137852600" 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=RCV000010531 OR RCV000010532 OR RCV001851781" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010531, RCV000010532, RCV001851781" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010531...</a>
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<p><a href="#131" class="mim-tip-reference" title="Nakao, R., Yanase, T., Sakai, Y., Haji, M., Nawata, H. <strong>A single amino acid substitution (gly743-val) in the steroid-binding domain of the human androgen receptor leads to Reifenstein syndrome.</strong> J. Clin. Endocr. Metab. 77: 103-107, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8325932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8325932</a>] [<a href="https://doi.org/10.1210/jcem.77.1.8325932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8325932">Nakao et al. (1993)</a> found a gly743-to-val (G743V) substitution in the androgen receptor in a 20-year-old male with partial androgen insensitivity syndrome (<a href="/entry/312300">312300</a>) manifesting gynecomastia, hypospadias, microphallus, absent pubic hair, and palpable mammary glands. The amino acid substitution arose from a G-to-T transversion in exon 5 of the AR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8325932" 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="#98" class="mim-tip-reference" title="Lobaccaro, J.-M., Lumbroso, S., Berta, P., Chaussain, J.-L., Sultan, C. <strong>Complete androgen insensitivity syndrome associated with a de novo mutation of the androgen receptor gene detected by single strand conformation polymorphism.</strong> J. Steroid Biochem. Molec. Biol. 44: 211-216, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096390</a>] [<a href="https://doi.org/10.1016/0960-0760(93)90081-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8096390">Lobaccaro et al. (1993)</a> found this mutation de novo in a French child with complete androgen insensitivity syndrome (<a href="/entry/300068">300068</a>) and negative receptor binding. They noted that the G743V change is in the hormone binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8096390" 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>.0057 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, GLY743GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852600 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852600;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=rs137852600" 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=rs137852600" 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=RCV000010533" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010533" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010533</a>
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<p>In a patient with complete androgen insensitivity syndrome (<a href="/entry/300068">300068</a>), <a href="#147" class="mim-tip-reference" title="Poujol, N., Lumbroso, S., Terouanne, B., Lobaccaro, J.-M. A., Bourguet, W., Sultan, C. <strong>Pathophysiology of androgen insensitivity syndromes: molecular and structural approaches of natural and engineered androgen receptor mutations at amino acid 743.</strong> J. Clin. Endocr. Metab. 87: 5793-5800, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12466388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12466388</a>] [<a href="https://doi.org/10.1210/jc.2002-020491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12466388">Poujol et al. (2002)</a> found a G-to-A transition in exon 5 of the AR gene that resulted in a gly743-to-glu (G743E) amino acid substitution. The patient was referred for primary amenorrhea, normal breast development, and complete absence of pubic and axillary hair at the age of 15 years. Plasma testosterone levels were within the range for normal males, and the karyotype was 46,XY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12466388" 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>.0058 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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AR, INS/DEL, EX5
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869320732 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320732;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=rs869320732" 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=rs869320732" 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=RCV000010534" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010534" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010534</a>
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<p><a href="#175" class="mim-tip-reference" title="Vilchis, F., Ramos, L., Kofman-Alfaro, S., Zenteno, J. C., Mendez, J. P., Chavez, B. <strong>Extreme androgen resistance in a kindred with a novel insertion/deletion mutation in exon 5 of the androgen receptor gene.</strong> J. Hum. Genet. 48: 346-351, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12908100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12908100</a>] [<a href="https://doi.org/10.1007/s10038-003-0036-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12908100">Vilchis et al. (2003)</a> studied a family in which 4 46,XY individuals in 3 sibships of 2 separate generations had complete androgen insensitivity. A novel insertion/deletion mutation in exon 5 of the AR gene was demonstrated. A deletion of 7 bp was replaced by an insertion of 11 nucleotides, which represented a duplication of the adjacent downstream sequence. The mutation resulted in a frameshift that introduced a premature TGA termination signal 9 codons downstream. The rearrangement predicted a truncation of the androgen receptor, thereby deleting a large portion of the ligand-binding domain. They suggested that this represented the first insertion/deletion mutation of the AR gene and that it had arisen by a slipped-strand mispairing mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12908100" 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>.0059 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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AR, SER740CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852601 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852601;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=rs137852601" 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=rs137852601" 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=RCV000010535" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010535" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010535</a>
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<p>In a 61-year-old man with partial androgen insensitivity, <a href="#146" class="mim-tip-reference" title="Pitteloud, N., Villegas, J., Dwyer, A. A., Crowley, W. F., Jr., McPhaul, M. J., Hayes, F. J. <strong>Acute stress masking the biochemical phenotype of partial androgen insensitivity syndrome in a patient with a novel mutation in the androgen receptor.</strong> J. Clin. Endocr. Metab. 89: 1053-1058, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001585</a>] [<a href="https://doi.org/10.1210/jc.2003-031373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15001585">Pitteloud et al. (2004)</a> identified a C-to-G transversion in exon 5 of the AR gene, changing serine to cysteine at codon 740 (S740C). Serine-740 is located in the ligand-binding domain of the AR protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15001585" 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>.0060 ANDROGEN INSENSITIVITY, PARTIAL</strong>
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AR, ALA645ASP, SHORT POLYGLYCINE REPEAT, LONG POLYGLUTAMINE REPEAT
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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> rs1800053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800053;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/rs1800053?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=rs1800053" 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=rs1800053" 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=RCV000010536 OR RCV000613283 OR RCV000824699 OR RCV000995934 OR RCV002512959 OR RCV003924823 OR RCV003982836" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010536, RCV000613283, RCV000824699, RCV000995934, RCV002512959, RCV003924823, RCV003982836" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010536...</a>
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<p><a href="#184" class="mim-tip-reference" title="Werner, R., Holterhus, P.-M., Binder, G., Schwarz, H.-P., Morlot, M., Struve, D., Marschke, C., Hiort, O. <strong>The A645D mutation in the hinge region of the human androgen receptor (AR) gene modulates AR activity, depending on the context of the polymorphic glutamine and glycine repeats.</strong> J. Clin. Endocr. Metab. 91: 3515-3520, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804045</a>] [<a href="https://doi.org/10.1210/jc.2006-0372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804045">Werner et al. (2006)</a> reported 2 unrelated 46,XY patients with undervirilization and genital malformations. Both patients had a short polyglycine (polyG) repeat of 10 residues and a relatively long polyglutamine (polyQ) repeat of 28 and 30 residues in the transactivation domain of the AR. In addition, both had a rare ala645-to-asp (A645D) substitution. In studies in transfected CHO cells, <a href="#184" class="mim-tip-reference" title="Werner, R., Holterhus, P.-M., Binder, G., Schwarz, H.-P., Morlot, M., Struve, D., Marschke, C., Hiort, O. <strong>The A645D mutation in the hinge region of the human androgen receptor (AR) gene modulates AR activity, depending on the context of the polymorphic glutamine and glycine repeats.</strong> J. Clin. Endocr. Metab. 91: 3515-3520, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804045</a>] [<a href="https://doi.org/10.1210/jc.2006-0372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804045">Werner et al. (2006)</a> found that a short polyG repeat downmodulated AR activity to approximately 60 to 65% of the wildtype receptor. This effect was aggravated by A645D in context of a long polyQ repeat to less than 50% activity. In contrast, in the context of a short polyQ and a short polyG repeat, the A645D mutation rescues AR activity to almost wildtype levels, demonstrating a contradictory effect of this mutation, depending on the size of the polymorphic repeats. <a href="#184" class="mim-tip-reference" title="Werner, R., Holterhus, P.-M., Binder, G., Schwarz, H.-P., Morlot, M., Struve, D., Marschke, C., Hiort, O. <strong>The A645D mutation in the hinge region of the human androgen receptor (AR) gene modulates AR activity, depending on the context of the polymorphic glutamine and glycine repeats.</strong> J. Clin. Endocr. Metab. 91: 3515-3520, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804045</a>] [<a href="https://doi.org/10.1210/jc.2006-0372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804045">Werner et al. (2006)</a> concluded that a combination of a short polyG repeat with a long polyQ repeat and an A645D substitution might explain the observed phenotype of their patients as a form of androgen insensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Gehring1974" class="mim-tip-reference" title="Gehring, U., Tomkins, G. M. <strong>Characterization of a hormone receptor defect in the androgen-insensitivity mutant.</strong> Cell 3: 59-64, 1974.">Gehring and Tomkins (1974)</a>; <a href="#Grino1988" class="mim-tip-reference" title="Grino, P. B., Griffin, J. E., Cushard, W. G., Jr., Wilson, J. D. <strong>A mutation of the androgen receptor associated with partial androgen resistance, familial gynecomastia, and fertility.</strong> J. Clin. Endocr. Metab. 66: 754-761, 1988.">Grino et al. (1988)</a>; <a href="#Hughes1986" class="mim-tip-reference" title="Hughes, I. A., Evans, B. A. J. <strong>Complete androgen insensitivity syndrome characterized by increased concentration of a normal androgen receptor in genital skin fibroblasts.</strong> J. Clin. Endocr. Metab. 63: 309-315, 1986.">Hughes and Evans
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(1986)</a>; <a href="#Jukier1984" class="mim-tip-reference" title="Jukier, L., Kaufman, M., Pinsky, L., Peterson, R. E. <strong>Partial androgen resistance associated with secondary 5-alpha-reductase deficiency: identification of a novel qualitative androgen receptor defect and clinical implications.</strong> J. Clin. Endocr. Metab. 59: 679-688, 1984.">Jukier et al. (1984)</a>; <a href="#Kaufman1984" class="mim-tip-reference" title="Kaufman, M., Pinsky, L., Bowin, A., Au, M. W. S. <strong>Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5-alpha-dihydrotestosterone and the synthetic androgen methyltrienolone.</strong> Am. J. Med. Genet. 18: 493-507, 1984.">Kaufman et al. (1984)</a>; <a href="#Kaufman1976" class="mim-tip-reference" title="Kaufman, M., Straisfeld, C., Pinsky, L. <strong>Male pseudohermaphroditism presumably due to target organ unresponsiveness to androgens: deficient 5-alpha-dihydrotestosterone binding in cultured skin fibroblasts.</strong> J. Clin. Invest. 58: 345-350, 1976.">Kaufman et al.
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(1976)</a>; <a href="#Keenan1974" class="mim-tip-reference" title="Keenan, B. S., Meyer, W. J., III, Hadjian, A. J., Jones, H. W., Migeon, C. J. <strong>Syndrome of androgen insensitivity in man: absence of 5-alpha-dihydrotestosterone binding protein in skin fibroblasts.</strong> J. Clin. Endocr. 38: 1143-1146, 1974.">Keenan et al. (1974)</a>; <a href="#Lin1981" class="mim-tip-reference" title="Lin, S.-Y., Ohno, S. <strong>The binding of androgen receptor to DNA and RNA.</strong> Biochim. Biophys. Acta 654: 181-186, 1981.">Lin and Ohno (1981)</a>; <a href="#Lubahn1988" class="mim-tip-reference" title="Lubahn, D. B., Joseph, D. R., Sullivan, P. M., Willard, H. F., French, F. S., Wilson, E. M. <strong>Cloning of human androgen receptor complementary DNA and localization to the X chromosome.</strong> Science 240: 327-330, 1988.">Lubahn et al.
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(1988)</a>; <a href="#Ohno1971" class="mim-tip-reference" title="Ohno, S. <strong>Simplicity of mammalian regulatory systems inferred by single gene determination of sex phenotypes.</strong> Nature 234: 134-137, 1971.">Ohno (1971)</a>; <a href="#Ohno1977" class="mim-tip-reference" title="Ohno, S. <strong>The Y-linked antigen locus and the X-linked Tfm locus as major regulatory genes of the mammalian sex determining mechanism.</strong> J. Steroid Biochem. 8: 585-592, 1977.">Ohno (1977)</a>; <a href="#Pinsky1984" class="mim-tip-reference" title="Pinsky, L., Kaufman, M., Killinger, D. W., Burko, B., Shatz, D., Volpe, R. <strong>Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor.</strong> Am. J. Hum. Genet. 36: 965-978, 1984.">Pinsky et al. (1984)</a>; <a href="#Pinsky1987" class="mim-tip-reference" title="Pinsky, L., Kaufman, M., Levitsky, L. L. <strong>Partial androgen resistance due to a distinctive qualitative defect of the androgen receptor.</strong> Am. J. Med. Genet. 27: 459-466, 1987.">Pinsky et al.
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(1987)</a>; <a href="#Pinsky1981" class="mim-tip-reference" title="Pinsky, L., Kaufman, M., Summitt, R. L. <strong>Congenital androgen insensitivity due to a qualitatively abnormal androgen receptor.</strong> Am. J. Med. Genet. 10: 91-99, 1981.">Pinsky et al. (1981)</a>; <a href="#Wilson1984" class="mim-tip-reference" title="Wilson, J. D., Carlson, B. R., Weaver, D. D., Kovacs, W. J., Griffin, J. E. <strong>Endocrine and genetic characterization of cousins with male pseudohermaphroditism: evidence that the Lubs phenotype can result from a mutation that alters the structure of the androgen receptor.</strong> Clin. Genet. 26: 363-370, 1984.">Wilson et al. (1984)</a>
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Abel, A., Walcott, J., Woods, J., Duda, J., Merry, D. E.
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<strong>Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice.</strong>
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Hum. Molec. Genet. 10: 107-116, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11152658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11152658</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11152658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Adachi, H., Kume, A., Li, M., Nakagomi, Y., Niwa, H., Do, J., Sang, C., Kobayashi, Y., Doyu, M., Sobue, G.
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<strong>Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death.</strong>
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Hum. Molec. Genet. 10: 1039-1048, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331614</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11331614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Aschim, E. L., Nordenskjold, A., Giwercman, A., Lundin, K. B., Ruhayel, Y., Haugen, T. B., Grotmol, T., Giwercman, Y. L.
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<strong>Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene.</strong>
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J. Clin. Endocr. Metab. 89: 5105-5109, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15472213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bailey, C. K., Andriola, I. F. M., Kampinga, H. H., Merry, D. E.
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<strong>Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.</strong>
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Hum. Molec. Genet. 11: 515-523, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875046</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Batch, J. A., Evans, B. A. J., Hughes, I. A., Patterson, M. N.
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<strong>Mutations of the androgen receptor gene identified in perineal hypospadias.</strong>
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J. Med. Genet. 30: 198-201, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8097257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8097257</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8097257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Batch, J. A., Williams, D. M., Davies, H. R., Brown, B. D., Evans, B. A. J., Hughes, I. A., Patterson, M. N.
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<strong>Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome.</strong>
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Hum. Molec. Genet. 1: 497-503, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1307250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1307250</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1307250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/1.7.497" target="_blank">Full Text</a>]
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Beitel, L. K., Kazemi-Esfarjani, P., Kaufman, M., Lumbroso, R., DiGeorge, A. M., Killinger, D. W., Trifiro, M. A., Pinsky, L.
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<strong>Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance.</strong>
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J. Clin. Invest. 94: 546-554, 1994.
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[<a href="https://doi.org/10.1172/JCI117368" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380050104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/5.2.265" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/1.4.255" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/me.2015-1079" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.9.7825" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.3.7333" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.85.21.8151" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh181" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/mend.15.1.0581" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.1.121" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0006-291x(03)00902-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.85.4.6561" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(98)70387-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.82.24.8345" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.17.1967" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.5.829" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0005-2787(81)90170-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.11.1799" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0960-0760(93)90081-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.86.23.9534" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/mend-2-12-1265" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.3353727" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI116271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/mend-4-8-1105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI114599" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20043" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature12451" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.212474399" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI28773" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0894-531" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41588-018-0120-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.5.5695" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2005-0432" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.10.7889" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2002-021947" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2004-1424" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI116269" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 07/13/2018
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Patricia A. Hartz - updated : 02/14/2018<br>Paul J. Converse - updated : 01/25/2017<br>Patricia A. Hartz - updated : 11/18/2016<br>Marla J. F. O'Neill - updated : 4/1/2014<br>Ada Hamosh - updated : 10/1/2013<br>Cassandra L. Kniffin - updated : 8/2/2011<br>Ada Hamosh - updated : 6/14/2011<br>George E. Tiller - updated : 2/23/2010<br>George E. Tiller - updated : 10/23/2009<br>John A. Phillips, III - updated : 1/15/2009<br>John A. Phillips, III - updated : 1/13/2009<br>John A. Phillips, III - updated : 6/24/2008<br>Patricia A. Hartz - updated : 4/9/2008<br>John A. Phillips, III - updated : 1/7/2008<br>Marla J. F. O'Neill - updated : 8/22/2007<br>Paul J. Converse - updated : 5/8/2007<br>John A. Phillips, III - updated : 4/9/2007<br>John A. Phillips, III - updated : 4/9/2007<br>George E. Tiller - updated : 1/16/2007<br>Cassandra L. Kniffin - updated : 12/13/2006<br>John A. Phillips, III - updated : 5/23/2006<br>Cassandra L. Kniffin - updated : 4/24/2006<br>John A. Phillips, III - updated : 4/5/2006<br>Marla J. F. O'Neill - updated : 3/23/2006<br>Marla J. F. O'Neill - updated : 3/13/2006<br>Patricia A. Hartz - updated : 11/10/2005<br>Cassandra L. Kniffin - reorganized : 10/28/2005<br>Cassandra L. Kniffin - updated : 10/14/2005<br>Patricia A. Hartz - updated : 9/21/2005<br>John A. Phillips, III - updated : 7/19/2005<br>John A. Phillips, III - updated : 7/13/2005<br>Cassandra L. Kniffin - updated : 6/27/2005<br>Victor A. McKusick - updated : 6/17/2005<br>George E. Tiller - updated : 4/22/2005<br>John A. Phillips, III - updated : 4/1/2005<br>George E. Tiller - updated : 3/21/2005<br>George E. Tiller - updated : 2/17/2005<br>John A. Phillips, III - updated : 8/2/2004<br>John A. Phillips, III - updated : 7/21/2004<br>Victor A. McKusick - updated : 6/15/2004<br>Cassandra L. Kniffin - updated : 11/24/2003<br>George E. Tiller - updated : 9/18/2003<br>Victor A. McKusick - updated : 8/27/2003<br>Victor A. McKusick - updated : 8/5/2003<br>John A. Phillips, III - updated : 7/30/2003<br>George E. Tiller - updated : 7/9/2003<br>John A. Phillips, III - updated : 3/27/2003<br>John A. Phillips, III - updated : 1/8/2003<br>Victor A. McKusick - updated : 1/8/2003<br>George E. Tiller - updated : 11/11/2002<br>George E. Tiller - updated : 10/3/2002<br>Victor A. McKusick - updated : 9/30/2002<br>Stylianos E. Antonarakis - updated : 9/20/2002<br>George E. Tiller - updated : 9/17/2002<br>George E. Tiller - updated : 8/21/2002<br>John A. Phillips, III - updated : 8/8/2002<br>John A. Phillips, III - updated : 8/8/2002<br>John A. Phillips, III - updated : 7/31/2002<br>John A. Phillips, III - updated : 7/25/2002<br>John A. Phillips, III - updated : 7/23/2002<br>Victor A. McKusick - updated : 3/4/2002<br>Victor A. McKusick - updated : 1/24/2002<br>John A. Phillips, III - updated : 11/7/2001<br>Michael B. Petersen - updated : 10/30/2001<br>Victor A. McKusick - updated : 10/15/2001<br>John A. Phillips, III - updated : 10/11/2001<br>John A. Phillips, III - updated : 8/8/2001<br>John A. Phillips, III - updated : 8/3/2001<br>John A. Phillips, III - updated : 7/26/2001<br>Victor A. McKusick - updated : 6/25/2001<br>George E. Tiller - updated : 3/12/2001<br>Carol A. Bocchini - updated : 2/22/2001<br>Victor A. McKusick - updated : 2/7/2001<br>Jane Kelly - updated : 1/18/2001<br>George E. Tiller - updated : 11/17/2000<br>John A. Phillips, III - updated : 8/9/2000<br>George E. Tiller - updated : 5/5/2000<br>John A. Phillips, III - updated : 3/31/2000<br>Wilson H. Y. Lo - updated : 3/21/2000<br>Armand Bottani - updated : 3/14/2000<br>Victor A. McKusick - updated : 2/16/2000<br>Victor A. McKusick - updated : 1/24/2000<br>Victor A. McKusick - updated : 12/22/1999<br>John A. Phillips, III - updated : 11/29/1999<br>Sonja A. Rasmussen - updated : 11/16/1999<br>Wilson H. Y. Lo - updated : 9/2/1999<br>Victor A. McKusick - updated : 4/23/1999<br>Victor A. McKusick - updated : 1/25/1999<br>John A. Phillips, III - updated : 9/29/1998<br>Victor A. McKusick - updated : 3/26/1998<br>John A. Phillips, III - updated : 3/18/1998<br>John A. Phillips, III - updated : 1/3/1998<br>Victor A. McKusick - updated : 11/26/1997<br>John A. Phillips, III - updated : 8/26/1997<br>Victor A. McKusick - updated : 6/12/1997<br>Victor A. McKusick - updated : 5/13/1997<br>Victor A. McKusick - updated : 3/21/1997<br>Victor A. McKusick - updated : 2/28/1997<br>John A. Phillips, III - updated : 12/20/1996<br>Cynthia K. Ewing - updated : 10/14/1996<br>John A. Phillips, III - updated : 9/21/1996
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</span>
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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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</span>
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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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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<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 : 07/12/2024
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 11/08/2023<br>carol : 11/07/2023<br>carol : 09/25/2022<br>carol : 02/14/2022<br>carol : 11/01/2019<br>carol : 06/13/2019<br>carol : 02/12/2019<br>carol : 09/11/2018<br>mgross : 07/13/2018<br>mgross : 02/14/2018<br>alopez : 02/02/2017<br>mgross : 01/25/2017<br>mgross : 11/18/2016<br>carol : 09/09/2016<br>carol : 04/02/2014<br>mcolton : 4/1/2014<br>alopez : 10/1/2013<br>terry : 4/1/2013<br>terry : 1/2/2013<br>alopez : 12/11/2012<br>terry : 11/28/2012<br>terry : 9/25/2012<br>terry : 6/7/2012<br>terry : 5/17/2012<br>carol : 2/27/2012<br>terry : 10/10/2011<br>alopez : 10/6/2011<br>joanna : 10/3/2011<br>wwang : 8/9/2011<br>ckniffin : 8/2/2011<br>ckniffin : 8/2/2011<br>ckniffin : 8/2/2011<br>alopez : 6/16/2011<br>terry : 6/14/2011<br>carol : 5/23/2011<br>carol : 5/11/2011<br>terry : 11/3/2010<br>terry : 9/9/2010<br>wwang : 2/25/2010<br>terry : 2/23/2010<br>wwang : 11/2/2009<br>terry : 10/23/2009<br>carol : 9/15/2009<br>wwang : 6/5/2009<br>ckniffin : 5/28/2009<br>carol : 2/20/2009<br>ckniffin : 2/20/2009<br>carol : 1/23/2009<br>alopez : 1/15/2009<br>alopez : 1/13/2009<br>alopez : 12/29/2008<br>mgross : 11/17/2008<br>wwang : 10/14/2008<br>terry : 9/26/2008<br>alopez : 6/26/2008<br>alopez : 6/24/2008<br>alopez : 5/2/2008<br>alopez : 5/1/2008<br>mgross : 4/11/2008<br>terry : 4/9/2008<br>carol : 1/7/2008<br>carol : 9/4/2007<br>wwang : 8/29/2007<br>terry : 8/22/2007<br>mgross : 5/14/2007<br>terry : 5/8/2007<br>carol : 4/9/2007<br>carol : 4/9/2007<br>wwang : 1/23/2007<br>terry : 1/16/2007<br>carol : 1/10/2007<br>wwang : 12/18/2006<br>ckniffin : 12/13/2006<br>carol : 11/27/2006<br>alopez : 8/23/2006<br>alopez : 5/23/2006<br>wwang : 5/9/2006<br>ckniffin : 4/24/2006<br>alopez : 4/5/2006<br>wwang : 3/23/2006<br>wwang : 3/23/2006<br>wwang : 3/17/2006<br>terry : 3/13/2006<br>mgross : 11/29/2005<br>mgross : 11/29/2005<br>terry : 11/10/2005<br>carol : 10/28/2005<br>ckniffin : 10/14/2005<br>wwang : 9/26/2005<br>wwang : 9/21/2005<br>alopez : 7/19/2005<br>alopez : 7/13/2005<br>carol : 7/5/2005<br>wwang : 7/1/2005<br>ckniffin : 6/27/2005<br>alopez : 6/21/2005<br>terry : 6/17/2005<br>tkritzer : 4/22/2005<br>alopez : 4/1/2005<br>alopez : 3/21/2005<br>terry : 3/16/2005<br>wwang : 2/22/2005<br>terry : 2/17/2005<br>terry : 2/17/2005<br>carol : 12/14/2004<br>alopez : 8/2/2004<br>ckniffin : 7/26/2004<br>alopez : 7/21/2004<br>tkritzer : 6/22/2004<br>terry : 6/15/2004<br>carol : 4/27/2004<br>tkritzer : 4/8/2004<br>carol : 12/8/2003<br>ckniffin : 11/24/2003<br>cwells : 11/5/2003<br>cwells : 9/18/2003<br>cwells : 8/29/2003<br>terry : 8/27/2003<br>tkritzer : 8/11/2003<br>tkritzer : 8/5/2003<br>tkritzer : 8/5/2003<br>alopez : 7/30/2003<br>terry : 7/28/2003<br>cwells : 7/9/2003<br>alopez : 3/27/2003<br>alopez : 1/8/2003<br>cwells : 1/8/2003<br>terry : 11/15/2002<br>alopez : 11/11/2002<br>alopez : 10/21/2002<br>carol : 10/18/2002<br>mgross : 10/18/2002<br>cwells : 10/3/2002<br>mgross : 10/1/2002<br>carol : 9/30/2002<br>mgross : 9/20/2002<br>cwells : 9/17/2002<br>cwells : 8/21/2002<br>cwells : 8/8/2002<br>cwells : 8/8/2002<br>tkritzer : 7/31/2002<br>tkritzer : 7/31/2002<br>tkritzer : 7/25/2002<br>tkritzer : 7/25/2002<br>tkritzer : 7/23/2002<br>carol : 3/14/2002<br>mgross : 3/11/2002<br>terry : 3/4/2002<br>carol : 2/21/2002<br>carol : 2/6/2002<br>mcapotos : 2/4/2002<br>terry : 1/24/2002<br>cwells : 11/9/2001<br>alopez : 11/8/2001<br>alopez : 11/7/2001<br>cwells : 10/30/2001<br>carol : 10/29/2001<br>mcapotos : 10/15/2001<br>alopez : 10/11/2001<br>alopez : 8/8/2001<br>alopez : 8/3/2001<br>alopez : 7/26/2001<br>mcapotos : 7/6/2001<br>mcapotos : 6/29/2001<br>terry : 6/25/2001<br>cwells : 3/27/2001<br>terry : 3/21/2001<br>cwells : 3/12/2001<br>cwells : 3/7/2001<br>mcapotos : 2/22/2001<br>mcapotos : 2/22/2001<br>carol : 2/22/2001<br>carol : 2/20/2001<br>mcapotos : 2/12/2001<br>mcapotos : 2/9/2001<br>terry : 2/7/2001<br>cwells : 1/23/2001<br>terry : 1/18/2001<br>mcapotos : 11/29/2000<br>terry : 11/17/2000<br>mgross : 8/9/2000<br>alopez : 5/5/2000<br>mgross : 4/28/2000<br>terry : 3/31/2000<br>carol : 3/21/2000<br>carol : 3/14/2000<br>mgross : 3/9/2000<br>terry : 2/16/2000<br>carol : 1/30/2000<br>terry : 1/24/2000<br>mcapotos : 1/7/2000<br>mcapotos : 1/4/2000<br>terry : 12/22/1999<br>alopez : 11/29/1999<br>alopez : 11/29/1999<br>mgross : 11/16/1999<br>mgross : 11/16/1999<br>carol : 9/2/1999<br>mgross : 5/12/1999<br>mgross : 4/29/1999<br>terry : 4/23/1999<br>mgross : 2/5/1999<br>terry : 1/25/1999<br>carol : 9/29/1998<br>alopez : 3/26/1998<br>terry : 3/20/1998<br>psherman : 3/18/1998<br>psherman : 3/18/1998<br>alopez : 1/27/1998<br>alopez : 1/27/1998<br>alopez : 1/26/1998<br>jenny : 12/2/1997<br>terry : 11/26/1997<br>jenny : 10/22/1997<br>alopez : 6/26/1997<br>carol : 6/23/1997<br>mark : 6/18/1997<br>terry : 6/12/1997<br>jenny : 5/21/1997<br>jenny : 5/21/1997<br>mark : 5/14/1997<br>mark : 5/14/1997<br>jenny : 5/13/1997<br>terry : 5/7/1997<br>terry : 3/21/1997<br>terry : 3/17/1997<br>mark : 2/28/1997<br>terry : 2/26/1997<br>jamie : 11/20/1996<br>jamie : 11/20/1996<br>mark : 11/19/1996<br>mark : 11/16/1996<br>mark : 11/16/1996<br>mark : 11/16/1996<br>mark : 11/8/1996<br>mark : 11/8/1996<br>mark : 11/8/1996<br>terry : 10/24/1996<br>jamie : 10/23/1996<br>jamie : 10/16/1996<br>jamie : 10/14/1996<br>mark : 9/29/1996<br>terry : 9/23/1996<br>carol : 9/21/1996<br>mark : 8/29/1996<br>mark : 3/30/1996<br>terry : 3/26/1996<br>terry : 3/12/1996<br>mark : 1/21/1996<br>terry : 1/18/1996<br>pfoster : 11/15/1995<br>mark : 10/2/1995<br>terry : 3/3/1995<br>davew : 7/28/1994<br>mimadm : 6/26/1994<br>warfield : 4/20/1994
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 313700
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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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ANDROGEN RECEPTOR; AR
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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DIHYDROTESTOSTERONE RECEPTOR; DHTR<br />
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NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 4; NR3C4
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: AR</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 122811000119101, 12313004, 230253001, 368851000119102;
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<strong>ICD10CM:</strong> E34.5, E34.50, E34.51, E34.52;
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<strong>ICD9CM:</strong> 259.5, 259.51, 259.52;
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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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<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: Xq12
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Genomic coordinates <span class="small">(GRCh38)</span> : X:67,544,021-67,730,619 </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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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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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="5">
|
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<span class="mim-font">
|
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Xq12
|
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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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{Prostate cancer, susceptibility to}
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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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301120
|
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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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X-linked
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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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<tr>
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<td>
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<span class="mim-font">
|
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Androgen insensitivity
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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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300068
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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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X-linked recessive
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Androgen insensitivity, partial, with or without breast cancer
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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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312300
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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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X-linked recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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Hypospadias 1, X-linked
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<span class="mim-font">
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300633
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X-linked recessive
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<span class="mim-font">
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3
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Spinal and bulbar muscular atrophy, X-linked 1
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<span class="mim-font">
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313200
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<span class="mim-font">
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X-linked recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The gene encoding androgen receptor (AR), alternatively known as the dihydrotestosterone receptor, is located on the X chromosome. It is mutant in the androgen insensitivity syndrome (AIS; 300068), formerly known as the testicular feminization syndrome (TFM), and in Kennedy spinal and bulbar muscular atrophy (SBMA; 313200). Clinical variants of the androgen insensitivity syndrome (partial androgen insensitivity) include the Reifenstein syndrome (312300).</p><p>The AR protein belongs to the class of nuclear receptors called activated class I steroid receptors, which also includes glucocorticoid receptor (GCCR; 138040), progesterone receptor (PGR; 607311), and mineralocorticoid receptor (NR3C2; 600983). These receptors recognize canonical androgen response elements (AREs), which are inverted repeats of 5-prime-TGTTCT-3-prime. The major domains of AR include N- and C-terminal activation domains, which are designated activation function-1 (AF-1) and AF-2, a ligand-binding domain, and a polyglutamine tract (Callewaert et al., 2003). </p>
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<strong>Cloning and Expression</strong>
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<p>Chang et al. (1988) and Lubahn et al. (1988) cloned human androgen receptor cDNAs. Lubahn et al. (1988) determined the complete coding sequence of the human androgen receptor and compared the deduced 919-amino acid sequence (98,999 Da) to the 902-amino acid sequence of rat AR (98,227 Da). Identical sequences were found in the DNA- and hormone-binding domains, with an overall homology of 85%. Chang et al. (1988) obtained cDNAs from human testis and rat ventral prostate cDNA libraries. The deduced amino acid sequence indicated the presence of a cysteine-rich DNA-binding domain that is highly conserved in all steroid receptors. The human cDNA was transcribed and the RNA product translated in cell-free systems to yield a 76-kD protein. The protein was immunoprecipitable by human autoimmune antibodies to the androgen receptor, and it bound androgens specifically and with high affinity. (Some older men with prostate cancer have high titers of autoimmune antibodies to androgen receptor (Liao and Witte, 1985).) Both Chang et al. (1988) and Lubahn et al. (1988) used AR as the symbol for androgen receptor. </p><p>The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains. The N-terminal domain, which serves a modulatory function, is encoded by exon 1 (1,586 bp). The DNA-binding domain is encoded by exons 2 and 3 (152 and 117 bp, respectively). The androgen-binding domain is encoded by 5 exons which vary from 131 to 288 bp in size.</p><p>In human prostate, the major AR mRNA species is 10 kb, whereas a less abundant mRNA is approximately 7 kb (Lubahn et al., 1988). In the prostate, AR is localized predominantly to nuclei of granular epithelial cells. Tilley et al. (1989) isolated a cDNA that encodes the complete human AR gene. The cDNA predicted a protein of 917 amino acids with a molecular mass of of 98,918 Da. Introduction of the cDNA into heterologous mammalian cells caused expression of high levels of a protein that binds dihydrotestosterone with the affinity, specificity, and sedimentation properties characteristic of the native receptor. Comparison with the amino acid sequence of previously cloned steroid hormone receptors showed a high degree of sequence conservation with the progesterone, glucocorticoid, and mineralocorticoid receptors in the putative hormone and DNA-binding domains. </p><p>Two naturally occurring hormone-binding forms of progesterone receptor (607311) have been identified. The A isoform is an N-terminally truncated version of the full-length B isoform. Several lines of evidence suggest that the 2 isoforms serve specific functions. Wilson and McPhaul (1994) demonstrated 2 forms of the androgen receptor protein in human genital skin fibroblasts. The apparent molecular masses were approximately 110 kD and 87 kD. The 87-kD isoform (AR-A) contained an intact C terminus but lacked the normal N terminus found in the 110-kD isoform (AR-B). AR-A is the same size as the mutant form of AR produced in fibroblasts from an androgen-resistant individual by initiation of AR synthesis at the first internal met188 residue of AR-B, as reported by Zoppi et al. (1993). The AR isoforms resembled the A and B forms of the progesterone receptor, which also are encoded by a single gene and differ by the absence or presence of an N-terminal segment. The A and B forms of the progesterone receptor differ in their ability to activate target genes and are regulated differently in various types of cells. The identification of similar forms of AR raised the possibility that the 2 isoforms also serve different functions. </p>
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<strong>Gene Function</strong>
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<p>Kang et al. (1999) demonstrated that the ARA54 gene (RNF14; 605675) can function as a coactivator for androgen-dependent transcription on both wildtype and mutant androgen receptor. In the presence of a certain amount of 17-beta-estradiol or hydroxyflutamide, the transcriptional activity of a specific AR mutant was significantly enhanced, whereas that of wildtype and another AR mutant was not. They therefore suggested that both ARA54 and the positions of the AR mutation might contribute to the specificity of AR-mediated transactivation. Coexpression of ARA54 with other AR coactivators, such as ARA70 (NCOA4; 601984) and SRC1 (NCOA1; 602691), showed additive stimulation of AR-mediated transactivation, indicating that these cofactors may function individually as AR coactivators to induce AR target gene expression. </p><p>Sullivan et al. (2000) demonstrated that the androgen receptor protein exists within acinar epithelial cell nuclei of the rat meibomian gland. In studies in rats and rabbits, they found evidence that the meibomian gland is an androgen target organ and that androgens influence the lipid profile within this tissue. </p><p>Shang et al. (2002) described distinct functions for cofactor proteins and gene regulatory elements in the assembly of AR-mediated transcription complexes. The formation of an activation complex involves AR, coactivators, and RNA polymerase II (pol II; see 180660) recruitment to both the enhancer and promoter, whereas the formation of a repression complex involves factors bound only at the promoter and not the enhancer. The results suggested a model for the functional coordination between the promoter and enhancer in which communication between these elements is established through shared coactivators in the AR transcription complex. </p><p>Lee et al. (2003) hypothesized that AR may modulate gene expression by enhancing the efficiency of transcriptional elongation. They demonstrated that coexpression of the second largest subunit of RNA polymerase II, RPB2 (POLR2B; 180661), enhanced AR transactivation. Coexpression with other RNA polymerase II subunits or TFIIB (GTF2B; 189963) did not enhance AR-mediated transcription. Lee et al. (2003) concluded that AR may interact with TFIIH (see 189968), P-TEFb (see CCNT2; 603862), and RPB2 to enhance transcription from AR target genes. </p><p>Metzger et al. (2003) found that AR and PRK1 (PRKCL1; 601032) interacted in vitro and in vivo. Stimulation of the PRK1 signaling cascade resulted in ligand-dependent superactivation of AR in human prostate carcinoma cells, and PRK1 promoted a functional complex of AR with the coactivator TIF2 (NCOA2; 601993). PRK1 signaling stimulated AR activity in the presence of adrenal androgens and in the presence of an AR antagonist. Metzger et al. (2003) concluded that AR is controlled by PRK1 signaling as well as by ligand binding. </p><p>Callewaert et al. (2003) found that deletion of the polyglutamine tract within the N-terminal domain of AR increased transactivation of the receptor through canonical AREs, and the effect appeared due to tighter interaction between the N- and C-terminal domains of AR. Deletion of the polyglutamine tract also increased recruitment of SRC1 to the N-terminal domain of AR. Transactivation of selective AREs, which contain direct rather than inverted repeats of 5-prime-TGTTCT-3-prime, were not influenced by deletion of the AR polyglutamine tract. Callewaert et al. (2003) hypothesized that AR transcriptional activity on selective AREs does not depend on interaction between the N- and C-terminal domains of AR. </p><p>Using microarray analysis of rat ventral prostate RNA following 5-alpha-dihydrotestosterone treatment, Nantermet et al. (2004) found that AR rapidly modulated the expression of genes involved in proliferation and differentiation. AR repressed expression of several key cell cycle inhibitors while modulating members of the Wnt (see 164820) and Notch (see 190198) signaling pathways, multiple growth factors, peptide hormone signaling systems, and genes involved in MAP kinase and calcium signaling. The data suggested that activity of p53 (191170) was negatively regulated by AR activation, even though p53 RNA was unchanged. Using LNCaP cells, Nantermet et al. (2004) determined that AR inhibited p53 protein accumulation in the nucleus, providing a posttranscriptional mechanism by which androgens control prostate cell growth and survival. </p><p>By SDS-PAGE and peptide mass fingerprinting, Ishitani et al. (2003) characterized human embryonic kidney cell nuclear proteins that interacted with purified AF-1 of AR. Proteins that interacted with AF-1 included nuclear RNA-binding protein NRB54 (NONO; 300084), polypyrimidine tract-binding protein-associated splicing factor (PSF, or SFPQ; 605199), paraspeckle protein-1 (PSP1, or PSPC1; 612408), and PSP2 (RBM14; 612409), which are assumed to be involved in pre-mRNA processing. Binding of NRB54 to AF-1 was ligand dependent, and AF-1 function was potentiated by NRB54. </p><p>Lee and Chang (2003) reviewed mechanisms implicated in the control of AR protein expression and degradation and their potential relationship to androgen-related diseases. </p><p>Mandrusiak et al. (2003) found that androgen receptor N-terminal fragments are a substrate for transglutaminase (see 190195). Western blots of the proteins following incubation with transglutaminase showed loss of several different epitopes of the AR, suggestive of transglutaminase crosslinking of the AR, which interferes with antibody recognition. HEK GFPu-1 cells expressing polyglutamine-expanded androgen receptor and transglutaminase exhibited ligand-dependent proteasome dysfunction; this effect was not observed in the presence of cystamine, a transglutaminase inhibitor. In addition, transglutaminase-mediated isopeptide bonds were detected in brains of SBMA transgenic mice, but not in controls, suggesting involvement of transglutaminase-catalyzed reactions in polyglutamine disease pathogenesis. Mandrusiak et al. (2003) hypothesized that crosslinked AR cannot be degraded by the proteasome and may obstruct the proteasome pore, preventing normal function. </p><p>Wang et al. (2005) found that AR regulation of PSA (KLK3; 176820) in LNCaP cells involved both a promoter-proximal sequence and an enhancer about 4 kb upstream. Recruitment of AR and essential coactivators at both sites created a chromosomal loop that allowed RNA polymerase II to track from the enhancer to the promoter. Phosphorylation of the RNA pol II C-terminal domain was required for RNA pol II tracking but not chromosomal looping. </p><p>Chiu et al. (2007) examined the roles of AR and the hepatitis B virus nonstructural protein HBx in hepatocellular carcinoma (114550), a disease that predominantly affects males. HBx increased the anchorage-independent colony formation potency of AR in a nontransformed mouse hepatocyte cell line. AR-mediated transcriptional activity was enhanced by HBx in an androgen concentration-dependent manner. Mutation analysis showed that HBx-enhanced AR gene transcriptional activity required intact HBx and the hinge region of AR. Immunoprecipitation and cell fractionation analyses revealed that HBx-AR interactions occurred mainly in the cytosol. HBx-enhanced AR activation involved SRC (190090) activity. Chiu et al. (2007) concluded that HBx is a noncellular positive coregulator of AR. </p><p>Using protein pull-down and coimmunoprecipitation analyses, Wang et al. (2012) found that activating transcription factor-3 (ATF3; 603148) interacted with AR. Mutation analysis revealed that the bZIP domain of ATF3 interacted with the DNA-binding and ligand-binding domains of AR. Binding of ATF3 inhibited interaction of AR with AREs in DNA and inhibited intramolecular interactions between the N- and C-terminal regions of AR. ATF3 did not interfere with binding between AR and androgen ligand, nor did it inhibit ligand-dependent nuclear translocation of AR. Expression of ATF3 repressed AR-mediated transactivation of an ARE reporter in a dose-dependent manner. Repression was independent of ATF3 transcriptional activity, but it required binding of ATF3 to AR, which blocked binding of AR to target promoters/enhancers. Knockdown of ATF3 via short hairpin RNA in human prostate cancer cell lines increased expression of AR-dependent genes, and knockout of Atf3 in mice promoted proliferation of prostate epithelial cells. </p><p>Yang et al. (2013) reported that 2 long noncoding RNAs (lncRNAs) highly overexpressed in aggressive prostate cancer, PRNCR1 (615452) and PCGEM1 (605443), bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated AR on enhancers and its association with DOT1L (607375) appear to be required for recruitment of the second lncRNA, PCGEM1, to the AR amino terminus, which is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus-2 (PYGO2; 606903) PHD domain enhances selective looping of AR-bound enhancers to target gene promoters in these cells. In resistant prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumor xenograft growth in vivo. Yang et al. (2013) concluded that these overexpressed lncRNAs can potentially serve as a required component of castration resistance in prostatic tumors. </p><p>Blessing et al. (2015) found that disruption of the pro-rich region within the N terminus of human AR reduced androgen-dependent proliferation and migration of human prostate cancer cells. Phage display analysis showed that SH3YL1 (617314) interacted with the AR pro-rich domain. Knockdown of SH3YL1 attenuated androgen-mediated cell growth and migration. RNA expression analysis revealed that SH3YL1 was required for induction of a subset of AR-modulated genes. UBN1 (609771), a key member of the histone H3.3 (see 601128) chaperone complex, was a transcriptional target of the SH3YL1/AR complex, correlated with aggressive prostate cancer in patients, and was necessary for maximal androgen-mediated proliferation and migration of prostate cancer cells. Blessing et al. (2015) concluded that the pro-rich N-terminal activation domain of AR, its SH3YL1 coregulator, and downstream transcriptional targets are involved in regulating processes important in prostate cancer pathology. </p><p>By coimmunoprecipitation analysis, Sun et al. (2016) showed that BAP18 (C17ORF49; 617215) interacted with AR in transfected HEK293 and in 22Rv1 prostate carcinoma cells. BAP18 enhanced AR activation of a reporter gene in an androgen-dependent manner. BAP18 facilitated recruitment of AR and the MLL1 (KMT2A; 159555) methyltransferase subcomplex to AREs in AR target genes, subsequently increasing histone H3 (see 602810) lys4 trimethylation and H4 (see 602822) lys16 acetylation. Sun et al. (2016) concluded that BAP18 is an epigenetic modifier that regulates AR-induced transactivation. </p><p>Using transcriptomic analysis, Zhang et al. (2018) identified ARLNC1 (618053) as a prostate lineage-specific lncRNA directly regulated by AR via an AR-binding site in the promoter region of ARLNC1. Further analysis analysis identified FOXA1 (602294) as an additional regulator of ARLNC1, with expression of AR and FOXA1 overlapping nearly exclusively in prostate tissue. ARLNC1 knockdown in human prostate cancer cells significantly decreased AR expression, suppressed genes positively regulated by AR, and upregulated genes negatively regulated by AR, suggesting a positive-feedback loop between ARLNC1 and AR. ARLNC1 and AR transcripts colocalized, and the authors found that nucleotides 700 to 1300 of ARLNC1 were critical for binding to the 3-prime UTR of the AR transcript. Tracking of the subcellular localization of AR transcripts in an ARLNC1-depleted prostate cancer cell line showed that ARLNC1 regulated the cytoplasmic levels of AR transcripts. Knockdown of ARLNC1 inhibited proliferation and promoted apoptosis in AR-positive prostate cancer cells, and tissue-specific knockdown of Arlnc1 in mice significantly decreased tumor growth compared with controls. </p><p><strong><em>Studies on the AR Protein with an Expanded Polyglutamine Repeat</em></strong></p><p>
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Choong et al. (1996) found an inverse relationship between AR CAG repeat length and AR mRNA and protein levels in an in vitro model using transient transfection of human AR expression vectors. Trinucleotide repeat lengths of 43 and 65 associated with X-linked spinal and bulbar muscular atrophy decreased AR mRNA and protein levels, but did not alter equilibrium binding affinity for a synthetic androgen or the AR transcriptional activity. These findings indicated that glutamate expansions of up to 66 residues in the first AR exon did not alter AR functional activity but did reduce AR mRNA and protein expression. </p><p>Butler et al. (1998) found that transfection of an SBMA mutant androgen receptor (52 CAG repeats) into mouse neuroblastoma cells enhanced the production of C-terminally truncated fragments of the androgen receptor protein. A 74-kD fragment was particularly prominent in cells expressing the SBMA androgen receptor. From its size, it could be deduced that the 74-kD fragment lacked the hormone-binding domain but retained the DNA-binding domain. The 74-kD fragment may, therefore, be toxic to motor neurons by initiating the transcription of specific genes in the absence of hormonal control. Immunofluorescence microscopy on transfected neuroblastoma cells showed that the wildtype androgen receptor translocated to the nucleus after hormone activation, whereas the SBMA androgen receptor was mainly localized in the cytoplasm in the form of dense aggregates with very little androgen receptor protein in the nucleus. The findings could explain the reduction in transcriptional activity of the SBMA mutant as compared with wildtype androgen receptor. </p><p>Kobayashi et al. (1998) showed that in vitro translated full-length AR proteins containing different sized polyglutamine repeats (24, 65, and 97 repeats, respectively) were specifically cleaved by recombinant caspase-3 (CASP3; 600636), liberating a polyglutamine-containing fragment, and that the susceptibility to cleavage was polyglutamine repeat length-dependent. These findings suggested that the AR protein is one of the 'death substrates' cleaved by caspase-3 and that caspase-3 may be involved in the pathogenesis of SBMA. Merry et al. (1998) found that transfection of a truncated AR protein with expanded CAG repeats into COS-7 cells resulted in increased cell death. Western blot analysis showed that the expanded protein underwent proteolytic cleavage within the polyglutamine tract and formed intracellular aggregates in a repeat length-dependent manner. </p><p>Simeoni et al. (2000) produced a model to study the effects of potentially 'neurotoxic' polyglutamine aggregates in SBMA using immortalized motoneuronal cells transfected with AR containing polyglutamine repeats of different sizes (zero, 23, or 46 repeats). Using chimeras of the modified AR protein and the green fluorescent protein (GFP), they showed that aggregate formation occurs when the polyglutamine tract is elongated and AR is activated by androgens. In the cells coexpressing AR with the polyglutamine of pathologic length (46 repeats) and the GFP, Simeoni et al. (2000) noted the presence of several dystrophic neurites. Cell viability analyses showed a reduced growth/survival rate in the cells expressing the polyglutamine of pathologic length, whereas testosterone treatment partially counteracted both cell death and the formation of dystrophic neurites. These observations indicated the lack of correlation between aggregate formation and cell survival, and suggested that neuronal degeneration in SBMA may be secondary to axonal/dendritic insults. </p><p>McCampbell et al. (2000) demonstrated that CREB-binding protein (CREBBP; 600140), a transcriptional coactivator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice, and tissue from patients with SBMA. Soluble levels of CREB-binding protein were reduced in cells expressing expanded polyglutamine despite increased levels of CREBBP mRNA. Overexpression of CREBBP rescued cells from polyglutamine-mediated toxicity in neuronal cell culture. The authors proposed a CREBBP-sequestration model of polyglutamine expansion disease. </p><p>Welch and Diamond (2001) used the wildtype glucocorticoid receptor (GR; 138040) and a mutated form of the GR (GR-delta-109-317) to study expanded polyglutamine AR protein in different cell contexts. The authors found that wildtype GR promoted soluble forms of the AR protein and prevented nuclear aggregation in NIH 3T3 cells and cultured neurons. In contrast, GR-delta-108-317 decreased polyglutamine protein solubility, and caused formation of nuclear aggregates in nonneuronal cells. Nuclear aggregates recruited the heat-shock protein Hsp70 (see 140550) more rapidly than cytoplasmic aggregates, and were associated with decreased cell viability. Limited proteolysis and chemical crosslinking suggested that unique soluble forms of the expanded AR protein may underlie these distinct biologic activities. The authors hypothesized that unique protein associations or conformations of expanded polyglutamine proteins may determine subsequent cellular effects such as nuclear localization and cellular toxicity. </p><p>Bailey et al. (2002) developed a cell culture system which afforded quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. The authors demonstrated that Hsp70 and its co-chaperone Hsp40 (see 604572) not only increased expanded repeat AR solubility, but enhanced the degradation of expanded repeat AR through the proteasome. Furthermore, these chaperones significantly decreased the half-life of an expanded repeat AR, suggesting that upregulation of molecular chaperones may be a potential therapeutic target for polyglutamine diseases. </p><p>RNA interference is a mechanism that appears to control unwanted gene expression in a wide range of species. To test if RNA interference can be used to specifically downregulate a human disease-related transcript, Caplen et al. (2002) devised Drosophila and human tissue culture models of SBMA. A variety of different double-stranded RNAs (dsRNAs) were assessed for the ability to inhibit expression of transcripts that included a truncated human androgen receptor gene containing different CAG repeat lengths (16 to 112 repeats). In mammalian cells, sequence-specific small dsRNAs of 22 nucleotides rescued the toxicity and caspase-3 activation induced by plasmids expressing a transcript encoding an expanded polyglutamine tract. </p><p>Lieberman et al. (2002) showed that the mouse MN-1 cultured cell line expressing the wildtype androgen receptor (with 24 CAG repeats) responded to ligand by showing trophic effects including prolonged survival in low serum, whereas cells expressing the mutant receptor (with 65 CAG repeats) did not show a robust trophic response. This partial loss of function correlated with decreased levels of the mutant protein due to its preferential degradation by the ubiquitin-proteasome pathway. Expression analysis using oligonucleotide arrays confirmed that the mutant receptor underwent a partial loss of function, and failed to regulate a subset of genes whose expression is normally affected by ligand activation of the wildtype receptor. The authors concluded that polyglutamine expansion alters androgen receptor function by promoting its degradation and by modifying its activity as a transcription factor. </p><p>Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes.' Taylor et al. (2003) showed that mutant GFP-tagged androgen receptor (AR-112Q) formed insoluble aggregates and was toxic to cultured transfected cells. Using molecular and pharmacologic interventions to disrupt aggresome formation, the authors found that aggresome-forming proteins had an accelerated rate of turnover which was slowed by inhibition of aggresome formation, became membrane-bound, and associated with lysosomal structures. Taylor et al. (2003) suggested that aggresomes may be cytoprotective and serve as cytoplasmic recruitment centers to facilitate degradation of toxic proteins. </p><p>In vitro, Szebenyi et al. (2003) showed that androgen receptor and huntingtin (613004) polypeptides containing pathogenic polyglutamine (polyQ) repeats directly inhibited both fast axonal transport and elongation of neuritic processes. The effects were greater with truncated polypeptides and occurred without detectable morphologic aggregates. </p><p>LaFevre-Bernt and Ellerby (2003) found that expression of an expanded AR protein with 112 CAG repeats in human kidney cells activated 3 MAP kinase pathways, causing increased levels of phosphorylation of p44/42 (601795), p38 (600289), and SAPK/JNK (601158). Only inhibition of the p44/42 MAP kinase pathway reduced cell death, reduced the cleavage of expanded AR, and decreased phosphorylation of the expanded AR. LaFevre-Bernt and Ellerby (2003) postulated that phosphorylation at serine-514 of the AR protein is repeat length-dependent, and that phosphorylation enhances the ability of caspase-3 to cleave AR and generate toxic polyQ fragments. </p><p>Buchanan et al. (2004) characterized a somatic AR gene mutation from a human prostate tumor that resulted in interruption of the polyQ tract by 2 nonconsecutive leucine residues (AR-polyQ2L). Compared with wildtype AR, AR-polyQ2L exhibited disrupted interdomain communication (N/C interaction) and a lower protein level but paradoxically had markedly increased transactivation activity. Molecular modeling and the response to cofactors indicated that the increased activity of AR-polyQ2L resulted from presentation of a more stable platform for the recruitment of accessory proteins than wildtype AR. Analysis of the relationship between polyQ tract length and AR function revealed a critical size (16 to 29 glutamines) for maintenance of N/C interaction. Since 91 to 99% of AR alleles in different racial/ethnic groups encode a polyQ tract in the range of 16 to 29 glutamines, Buchanan et al. (2004) suggested that N/C interaction may have been preserved as an essential component of androgen-induced AR signaling. </p><p>Ranganathan et al. (2009) found that constitutive and doxycycline-induced expression of mutant AR with 65 CAG repeats (AR-65Q) in MN-1 and PC12 cells, respectively, were associated with depolarization of the mitochondrial membrane. This was mitigated by cyclosporine A, which inhibits opening of the mitochondrial permeability transition pore. Expression of AR-65Q in the presence of ligand resulted in an elevated level of reactive oxygen species, which was blocked by treatment with the antioxidants coenzyme Q10 and idebenone. The 65Q-mutant AR protein in MN-1 cells also resulted in increased Bax (600040), caspase-9 (CASP9; 602234), and caspase-3 (CASP3; 600636). There was altered expression of peroxisome proliferator-activated receptor gamma coactivator-1A (PPARGC1A; 604517) and SOD2 (147460) in affected tissues of SBMA knockin mice. Subcelluar fractionation and electron microscopy of MN-1 and PC12 cells showed that AR-65Q mutant associated with mitochondria. Ranganathan et al. (2009) concluded that there is mitochondrial dysfunction in SBMA cells and animal models, either through indirect effects on the transcription of nuclear-encoded mitochondrial genes or through direct effects of the mutant AR protein on mitochondria, or both. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>By somatic cell hybridization, Migeon et al. (1981) found that the androgen receptor locus is located between Xq13 and Xp11 and is proximal to the locus for PGK (311800). It may be located in the Xq11 region, judging by the findings in 1 rearrangement with a break there. Lack of complementation with cells from Tfm of the mouse indicated homology. Rearrangement must have occurred in evolution, however, because the Tfm locus is not near the centromere in the mouse. Findings consistent with localization of the human TFM locus to proximal Xq near the centromere were reported by Wieacker et al. (1985) who found a carrier woman heterozygous for a RFLP of a probe called p8, localized between Xcen and Xq13; 4 affected children had inherited the same p8 allele. </p><p>In 2 families with testicular feminization and 1 family with Reifenstein syndrome, Wieacker et al. (1987) found close linkage (indeed, no recombination) between the disease phenotype and DNA marker DXS1. Assuming that the 2 disorders are allelic, the summarized data led to a maximum lod score of 3.5 at theta = 0.0. </p><p>Lubahn et al. (1988) cloned human AR genomic DNA from a flow-sorted human X chromosome library by using a consensus nucleotide sequence from the DNA-binding domain of the family of nuclear receptors. They localized the gene to the region between the centromere and Xq13 by studying human-rodent hybrids in which the human X chromosome was fragmented. Using a cloned cDNA for AR, Brown et al. (1989) localized the AR gene to Xq11-q12 by analysis of somatic cell hybrid panels segregating portions of the X chromosome. They also found a RFLP that should be useful in linkage analysis of various forms of inherited androgen insensitivity. </p><p>In the most extensively affected kindred known with complete androgen insensitivity (CAIS), one living in the Dominican Republic, Imperato-McGinley et al. (1990) found linkage to DXS1 and PGK1, localizing the AR gene to an area between Xq11 and Xq13. Linkage between DXS1 and AR showed a peak lod score of 3.2 at theta = 0.06. No recombination was found between PGK1 and AR; peak lod score was 2.9 at theta = 0.0. Although both AR and PGK1 are distal to DXS1, it was not possible to determine the sequence of the two. Using 3 cDNA probes spanning various parts of the AR gene, they could demonstrate no abnormality in restriction fragment patterns, suggesting that the gene defect is not a deletion but rather a point mutation or a small insertion/deletion. </p>
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<strong>Molecular Genetics</strong>
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<p>Patterson et al. (1994) described a database of AR gene mutations, which included 114 unique mutations. Gottlieb et al. (1996) described the latest version of their AR mutation database which contained 212 entries representing 239 patients with androgen insensitivity syndrome (300068) or prostate cancer (301120) bearing 155 different AR mutations. Gottlieb et al. (1997) stated that the number of reported mutations in their database had risen from 212 to 272. To complement the database, they had constructed mutation maps for AIS phenotypes and for prostate cancer, classified the number and variety of mutation types, and tabulated information on the multiplicity of the CpG-site mutations. </p><p>In an update on the AR gene mutation database, Gottlieb et al. (2004) stated that the reported mutations had risen from 374 to 605, and the number of AR-interacting proteins described had increased from 23 to 70, over the previous 3 years. In addition, silent mutations had been reported in both androgen insensitivity syndrome and prostate cancer cases. The database also incorporated information on spinobulbar muscular atrophy (SBMA; 313200), which is caused by a CAG repeat in exon 1 of the AR gene, as well as CAG repeat length variations associated with risk for breast, endometrial, colorectal, and prostate cancer, as well as for male infertility. </p><p>Mooney et al. (2003) presented a method for distinguishing disease-causing mutations in the AR gene from mutations that are associated with disease but have no causal role. They used a measure of nucleotide conservation among similar genes as well as AR mutations previously identified as disease-causing in various forms of AIS and prostate cancer. The degree of conservation of disease-causing mutations correlated with the severity of the AIS phenotype, and experimentally proven prostate cancer-linked mutations were found to occur in highly conserved regions of the gene. </p><p>To investigate whether androgen sensitivity, indicated by the length of the CAG repeat in the AR gene, has a role in the pathogenesis of premature adrenarche, Lappalainen et al. (2008) performed a cross-sectional association study among 73 Finnish Caucasian children with premature adrenarche (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). The methylation-weighted CAGn (mwCAGn) was determined via CAGn length and X-chromosome inactivation analysis, and clinical phenotype recorded. Subjects with premature adrenarche had significantly shorter mwCAGn than controls (mean difference (95% confidence interval); 0.76 (0.14-1.38); P = 0.017). AR gene mwCAGn did not correlate with androgen or SHBG (182205) levels in either group. The mean of mwCAGn was significantly shorter in children with premature adrenarche with lower BMI compared with those with higher BMI and in those with premature adrenarche and lower BMI compared with healthy children with same BMI. Lappalainen et al. (2008) concluded that AR gene CAGn polymorphism may have a significant role in the pathogenesis of premature adrenarche, especially in lean children. </p><p><strong><em>Hypospadias and Cryptorchidism</em></strong></p><p>
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Because polymorphic CAG and GGN segments regulate AR function, Aschim et al. (2004) investigated if there was an association between these polymorphisms and hypospadias (300633) and cryptorchidism (see 219050). Genotyping was performed by direct sequencing of DNA from patients diagnosed with hypospadias and cryptorchidism and controls. The subjects with hypospadias were divided into subgroups of glanular, penile, and penoscrotal hypospadias. Median GGN lengths were significantly higher (24 vs 23) among subjects with cryptorchidism compared with controls (P = 0.001) and those with penile hypospadias, compared with either controls (P = 0.003) or glanular and penoscrotal hypospadias combined (P = 0.018). The frequency of cases with GGN 24 or more vs GGN = 23 differed significantly among those with cryptorchidism (65/35%) compared with controls (31/54%) (P = 0.012), and among subjects with penile hypospadias (69/31%) compared with either controls (P = 0.035) or glanular or penoscrotal hypospadias combined (32/55%) (P = 0.056). There were no significant differences in CAG lengths between the cases and controls. </p><p><strong><em>Androgen Insensitivity Syndrome</em></strong></p><p>
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McPhaul et al. (1992) analyzed the nucleotide sequence of the AR gene from 22 unrelated subjects with substitution mutations of the hormone-binding domain. Eleven had the phenotype of complete testicular feminization, 4 had incomplete testicular feminization, and 7 had Reifenstein syndrome. The functional defect included absence of ligand binding in 10 subjects and qualitative or quantitative defects in binding in 10 and 2 subjects, respectively. They observed that of 19 of the 21 substitution mutations (90%) clustered in 2 regions that account for approximately 35% of the hormone-binding domain, namely, between amino acids 726 and 772 and between amino acids 826 and 864. The fact that one of these regions is homologous to a region of the human thyroid hormone receptor that is a known cluster site for mutations that cause thyroid hormone resistance implies that the localization of mutations in the AR gene is not coincidence. </p><p>In a family in which 3 members had the complete form of the androgen insensitivity syndrome, Quigley et al. (1992) found complete deletion of the AR gene in affected persons and showed that the mutation had originated in the germline of the maternal great-grandfather of the index patient. Quigley et al. (1992) stated that mutation analysis had been performed in at least 60 unrelated persons and that in about half, a distinct single basepair mutation had been identified; the mutation produced an alteration in amino acid sequence, introducing a premature termination codon, or, in one case, resulting in aberrant mRNA splicing (Ris-Stalpers et al., 1990). Complete or partial gene deletions appear to be a rare molecular cause of the androgen insensitivity syndrome. Quigley et al. (1992) pointed out that the affected individuals in their family had sparse, fine, blond vellus hair over the labia majora and emphasized that this should not be referred to as pubic hair. The pubertal transformation of vellus hair into the longer, coarser, darker terminal hair characteristic of adult pubic and axillary regions is androgen dependent. They suggested that the term 'sparse pubic hair' be used only in reference to hair of the same quality as normal androgen-dependent terminal hair but of diminished quantity, and that the term complete androgen insensitivity syndrome be reserved for those patients with complete absence of true sexual hair. </p><p>McPhaul et al. (1993) summarized the spectrum of AR gene mutations in 31 unrelated subjects with various forms of androgen resistance syndrome. Most of the mutations were due to nucleotide changes that caused premature termination codons or single amino acid substitutions within the open reading frame, and most of these substitutions were localized in 3 regions of the androgen receptor: the DNA-binding domain and 2 segments of the androgen-binding domain. Less frequently, partial or complete gene deletions had been identified. Sultan et al. (1993) tabulated 45 different mutations in the AR gene observed in patients with the complete androgen insensitivity syndrome, and 27 mutations found in patients with partial androgen insensitivity syndrome (PAIS). </p><p>In 5 subjects in 4 families with androgen insensitivity, Murono et al. (1995) identified mutations in the steroid-binding domain of the androgen receptor. Four of the subjects, including 2 sibs, had CAIS; 1 subject with ambiguous genitalia had a missense mutation (313700.0008). </p><p>Rodien et al. (1996) reported striking variations in the phenotypes of 3 related patients with a mutation in the AR gene (M780I; 313700.0039). Two of the affected family members had a feminine phenotype with Tanner stage 2 pubic hair, suggesting nearly complete androgen insensitivity. The third subject was male with perineoscrotal hypospadias and cryptorchidism, suggesting reduced but residual androgen sensitivity. Genital skin fibroblasts were analyzed for 5-alpha-reductase activity, and the binding capacity of the androgen receptor was higher in the male than in the 2 patients with female phenotypes. That the same mutation in different affected 46,XY members of the same family can cause variable clinical phenotypes suggests that the AR genotype does not accurately predict the phenotype in all families with androgen insensitivity. </p><p>Jakubiczka et al. (1997) identified mutations in the AR gene in 7 of 14 patients affected with complete androgen insensitivity. The authors made the following conclusions: major structural abnormalities such as deletions have been reported in only a few cases of CAIS. When both DNA- and steroid-binding domains are deleted, complete androgen resistance results. Minor structural abnormalities such as deletions or insertions of 1 or a few nucleotides are also rare. If the reading frame is disturbed, CAIS results, as is the case in the testicular feminization mouse. Single-base mutations are the most common type in the AR gene. </p><p>Premature stop codons of the AR gene are usually associated with complete androgen insensitivity syndrome. Holterhus et al. (1997) identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene (313700.0042) who presented with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. Examination of the sequencing gel identified a wildtype allele, indicating mosaicism. In addition, elimination of the unique AftII recognition site induced by the mutation was incomplete, thus confirming mosaicism. Normal androgen binding studies demonstrated expression of the wildtype AR in the patient's genital skin fibroblasts. Holterhus et al. (1997) concluded that somatic mosaicism of the AR gene shifts the phenotype to a higher degree of virilization than expected from the genotype of the mutant allele alone. </p><p>McPhaul et al. (1997) used a recombinant adenovirus to deliver an androgen-responsive gene in fibroblast cultures in order to assay AR function in normal subjects and patients with different forms of androgen resistance. They studied 3 groups of patients with known or suspected defects in AR function, including those with Reifenstein syndrome, spinobulbar muscular atrophy, and severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal controls and that of patients with complete testicular feminization. The authors concluded that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including 2 with a normal AR gene sequence. </p><p>Hiort et al. (1998) demonstrated that de novo and, in particular, somatic new mutations, occur at an unexpectedly high rate in AIS. In the AR gene mutation database maintained in Montreal, Gottlieb et al. (2001) found 25 cases where different degrees of androgen insensitivity were caused by identical mutations in the AR gene. In 5 of these cases, the phenotypic variability was due to somatic mosaicism, that is, somatic mutations that occurred in only certain cells of androgen-sensitive tissue. </p><p>Holterhus et al. (1999) reported a 46,XY newborn with ambiguous genitalia and mutation in the AR gene (313700.0005). Direct DNA sequencing and only incomplete NlaIII digestion of a genomic DNA/PCR fragment containing the mutation displayed the coexistence of mutant and wildtype androgen receptor alleles. Because the patient was the only affected family member and because only the wildtype androgen receptor DNA sequence was present in the mother, Holterhus et al. (1999) concluded that the mutation had occurred de novo at the postzygotic stage, leading to somatic mosaicism. Analysis of methyltrienolone binding on the patient's cultured genital skin fibroblasts revealed the expression of 2 functionally different androgen receptors. This finding confirmed somatic mosaicism in the patient and indicated that the most likely molecular mechanism responsible for the unexpectedly strong virilization of the proband is the androgen action through the wildtype AR expressed by part of the somatic cells. </p><p>Holterhus et al. (1999) presented the clinical and molecular spectrum of somatic mosaicism in 5 patients. They suggested that functionally relevant expression of the wildtype androgen receptor needs to be considered in all mosaic individuals and that treatment should be adjusted accordingly. </p><p>Holterhus et al. (2000) reported a family with 4 affected individuals, 3 brothers and their uncle, displaying strikingly different external genitalia. They detected the same leu712-to-phe (L712F; 313700.0050) AR mutation in each subject. They demonstrated that the 712F AR could switch its function from subnormal to normal within the physiologic concentration range of testosterone. The authors concluded that, taking into account the well-documented individual and time-dependent variation in testosterone concentration in early fetal development, their observations illustrated the potential impact of varying ligand concentrations for distinct cases of phenotypic variability in AIS. </p><p>McPhaul and Griffin (1999) reviewed the spectrum of AR defects that cause male phenotypic abnormalities, as well as the clinical characteristics of the heterogeneous AR mutations, including their effects on AR protein structure and their frequencies and gene locations. </p><p>Poujol et al. (2002) integrated clinical, molecular, and structural data in an investigation into the characteristics of AR ligand binding and activation. They looked for residues substituted in AIS that are conserved among the different AR species but that diverge in the other steroid receptors, thus suggesting a role in androgen-binding specificity. Of the residues fitting these characteristics, they focused on the glycine at position 743, for which the natural substitutions glutamic acid (G743E; 313700.0057) and valine (G743V; 313700.0056) have been associated with different androgen resistance phenotypes. The consequences of both substitutions were evaluated along with those of a manufactured minimal glycine-to-alanine mutation. The gradual impairment of binding and trans-activation efficiencies in AR mutants ranging from alanine to valine and subsequently glutamic acid were highlighted by in vitro experiments. Structural analyses showed the consequences of these substitutions at the atomic level and suggested a difference in local organization among the nuclear receptor superfamily. The authors concluded that this integrative approach provides a useful tool for further investigations into the AR structure-function relationship in AIS. </p><p>Xu et al. (2003) described a 3-month-old girl with CAIS in whom the diagnosis was made during elective repair of inguinal hernia, which had been noted shortly after birth. She had a 46,XY karyotype with inversion of the X chromosome with one break disrupting the AR gene. Curiously, the phenotypically normal mother also carried the inversion in one X chromosome; a maternal aunt had CAIS and a 46,inv(X),Y karyotype. At the age of 5 years this aunt had undergone repair of inguinal hernias, at which time testes were identified. She underwent gonadectomy 1 year later because of concerns of potential malignancy. At age 16 years she had primary amenorrhea and a height of 180 cm. </p><p>Melo et al. (2003) studied 32 subjects with male pseudohermaphroditism due to androgen insensitivity syndrome from 20 families, 9 with CAIS and 11 with PAIS. They analyzed the entire coding region of the androgen receptor gene, and found mutations in all families with CAIS and in 8 of the 11 families with PAIS. They identified 15 different mutations, including 5 that had not been described. They compared detailed clinical and hormonal features with genotype in 25 subjects with AIS and confirmed these by mutation analysis. </p><p>Pitteloud et al. (2004) reported a 61-year-old man with androgen insensitivity and coincidental functional hypogonadotropic hypogonadism. While functional hypogonadotropic hypogonadism is not a well-recognized entity in males, major stress has been reported to cause transient suppression of the hypothalamic-pituitary-gonadal axis in men. The patient was noted to have undervirilization, minimal pubertal development, hypogonadal testosterone, and low gonadotropin levels consistent with congenital hypogonadotropic hypogonadism during a hospital admission for myocardial infarction. The patient was found to have PAIS due to a ser740-to-cys mutation (313700.0059) in the ligand-binding domain of the AR. Subsequent studies confirmed that he had the characteristic gonadotropin and sex steroid abnormalities of PAIS. The authors concluded that this was the first reported case of PAIS presenting with a reversible hypogonadotropic biochemical profile triggered by an acute illness and corticosteroid therapy. </p><p>Kohler et al. (2005) noted that in 70% of AIS cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life, because both mutant and wildtype receptors are expressed, and genetic counseling. The authors reported 6 patients with AIS due to somatic mutations of the AR and 1 mother with somatic mosaicism who transmitted the mutation twice. Of the 4 patients with PAIS, 3 presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wildtype AR for virilization because the same mutations, when they are inherited, lead to CAIS. They also reported 2 novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wildtype receptor does not always lead to virilization. When a germline de novo AR mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low. </p><p><strong><em>Spinal and Bulbar Muscular Atrophy</em></strong></p><p>
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La Spada and Fischbeck (1991) and La Spada et al. (1991) presented evidence that X-linked spinal and bulbar muscular atrophy (SBMA; 313200) is due to a mutation in the polyglutamine tract encoded by the first exon of the AR gene (313700.0014). The mutations consisted of increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disorder, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses; maximum lod score = 13.2 at theta = 0. Eleven different disease alleles were observed, indicating that the association was not likely to represent linkage disequilibrium. As reviewed by Griffin (1992), the 'clinical spectrum' of androgen resistance already included infertile male syndrome and undervirilized male syndrome; the new finding extended the spectrum. </p><p>Caskey et al. (1992) reviewed triplet repeat mutations identified in 2 of the most common heritable disorders, fragile X syndrome (300624) and myotonic dystrophy (160900), and in SBMA. Other similarities to the fragile X syndrome and myotonic dystrophy were pointed out by Biancalana et al. (1992) in a family with affected members in 4 generations: the mutant allele was unstable upon transmission from parent to child, with a documented variation from 46 to 53 CAG repeats and a tendency to increase in size (7 increases and a single decrease in 17 events), which appeared stronger upon transmission from a male than from a female. There was also evidence for limited somatic instability of the abnormal allele, with observable variation of up to 2 to 3 repeats. </p><p><strong><em>Prostate Cancer</em></strong></p><p>
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In 1 of 26 specimens of untreated organ-confined stage B prostate cancer, Newmark et al. (1992) identified a somatic mutation in the AR gene (313700.0013) in a highly conserved region within the hormone-binding domain. An abundance of the mutated fragment indicated its presence in cells with a growth advantage. The authors postulated that somatic mutation in the AR gene leading to persistent expression could give rise to androgen-independent prostate cancer. </p><p>The length of a polymorphic CAG repeat sequence occurring in the androgen receptor gene is inversely correlated with transcriptional activity by the androgen receptor. Men who possess exceptionally long CAG repeat lengths experience clinical androgen insensitivity, presumably related to reduced transcriptional activity of the receptor. Prostate carcinogenesis is dependent on androgens. Because shorter CAG repeat lengths are associated with high transcriptional activity of AR, Irvine et al. (1995) proposed that men with shorter repeat lengths will be at higher risk for prostate cancer. Some indirect evidence is consistent with this hypothesis. African Americans, who have generally shorter CAG repeat lengths in the AR gene, have a higher incidence and mortality rate from prostate cancer (Coetzee and Ross, 1994). Moreover, because of X linkage, a history of disease in a brother carries greater risk than paternal history. Against this background, Giovannucci et al. (1997) conducted within the Physician's Health Study a nested case-controlled study of 587 newly diagnosed cases of prostate cancer detected between 1982 and 1995, and 588 controls without prostate cancer. They found an association between fewer androgen receptor gene CAG repeats and higher risk of total prostate cancer. In particular, a shorter CAG repeat sequence was associated with cancers characterized by extraprostatic extension, distant metastases, or high histologic grade. Variability in the CAG repeat length was not associated with low-grade or low-stage disease. </p><p>To test for an association between clinical parameters of human prostate cancer and CAG repeat length, Hardy et al. (1996) analyzed normal lymphocyte DNA from 109 patients. The median age of patients was 63 years (range, 42 to 83), with 104 Caucasian, 2 African American, 1 Asian, and 2 of other racial origin. The median repeat length was 25, 22, 22, and 23 for patients presenting with stage A, B, C, and D disease, respectively. A significant correlation between CAG repeat length and age at onset was observed, whereas correlations with stage, level of prostate-specific antigen at diagnosis, and time to prostate-specific antigen relapse were not significant. Shorter CAG repeat lengths may be associated with the development of prostate cancer in men at a younger age. </p><p>Chang et al. (2002) found significantly increased frequencies of AR alleles carrying 16 or less GGC repeats in 159 independent hereditary prostate cancer cases (71%) and 245 sporadic prostate cancer cases (68%) compared with 211 controls (59%). No evidence for association between CAG repeats and prostate cancer risk was observed. Similar results were found with a test for linkage by parametric analysis and the male-limited X-linked transmission/disequilibrium test. </p><p><strong><em>Other Male-Specific Phenotypes Associated with Expanded Polyglutamine Repeat in the AR Gene</em></strong></p><p>
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Macke et al. (1993) used 3 complementary approaches to test the hypothesis that sequence variation in the AR gene plays a causal role in the development of male sexual orientation: linkage analysis using pairs of homosexual brothers, measurement of repeat lengths in tracts of single amino acids that are known to be highly variable in the population, and direct screening for nucleotide sequence changes. The analyses showed that homosexual brothers are as likely to be discordant as concordant for androgen receptor alleles; there are no large-scale differences between the distributions of polyglycine or polyglutamine tract lengths in the homosexual and control groups; and coding region sequence variation is not commonly found within the androgen receptor gene of homosexual men. The denaturing gradient gel electrophoresis (DGGE) screen identified 2 rare amino acid substitutions, ser205-to-arg and glu793-to-asp, the biologic significance of which was unknown. </p><p>Zhang et al. (1994) studied the instability of CAG trinucleotide repeats in the human AR gene by typing approximately 4,300 human sperm. While the mutation rate for 20- to 22-repeat alleles was similar to that shown by family analysis, alleles with 28 to 31 repeats had a 4.4 times greater rate of mutation, with contractions outnumbering expansions 9 to 1. The authors suggested that disease-causing alleles may be susceptible to 2 different mutational mechanisms, one primarily resulting in contraction and another leading to trinucleotide expansion. </p><p>Tut et al. (1997) hypothesized that changes in the AR gene could have a role in some cases of male infertility associated with impaired spermatogenesis. To test this hypothesis, they examined the lengths of the polyglutamine and polyglycine repeats in 153 patients with defective sperm production and compared them to those of 72 normal controls of proven fertility. There was no significant association between the polyglycine tract and infertility. However, patients with 28 or more glutamines in their AR had a greater than 4-fold (95% CI, 4.9 to 3.2) increased risk of impaired spermatogenesis, and the more severe the spermatogenic defect, the higher the proportion of patients with a longer Gln repeat. The risk of defective spermatogenesis was halved when the polyglutamine tract was short (23 or less glutamines). Whole-cell transfection experiments using AR constructs harboring 15, 20, or 31 Gln repeats and a luciferase reporter gene with an androgen response element promoter confirmed an inverse relationship between Gln number and trans-regulatory activity. Immunoblot analyses indicated that the reduced androgenicity of the ARs with longer Gln repeats was unlikely to be due to a change in AR protein levels. The authors concluded that there is a direct relation between the length of the AR polyglutamine tract and the risk of defective spermatogenesis that is attributable to the decreased AR functional competence that occurs with longer Gln tracts. </p><p>Dowsing et al. (1999) characterized the androgen gene in 35 male patients with infertility. Thirty had idiopathic azoospermia or oligozoospermia, and these men were found to have significantly longer CAG repeat tracts than controls (mean 23.2 vs 20.5; p = 0.0001). The odds of having CAG repeat lengths of 20 were 6-fold higher for fertile men than for men with a spermatogenic disorder. </p><p>Kooy et al. (1999) reported 3 brothers with mental retardation, behavior problems, marfanoid habitus, and normal male genitalia who had a contracted CAG repeat in their AR genes (8 repeats compared to the 11 to 33 repeats normally seen). The authors concluded that a causative relationship between a short CAG repeat in the AR gene and the observed phenotype could not be excluded. </p><p>Lim et al. (2000) examined whether longer AR(Gln)n repeats are associated with moderate to severe undermasculinization. Clinical features among the 78 undermasculinized 46,XY males studied included partly fused or unfused scrotum, micropenis, and hypospadias. The average AR(Gln)n length of the undermasculinized group (median 25, interquartile range 23-26) was significantly greater than that of the 850 controls (median 23, interquartile range 22-26, p = 0.002). The odds ratio of having 23 or more repeats (as opposed to 22 or fewer repeats) in the undermasculinized group was 2.51 (95% CI, 1.41-4.48). The estimated increase in the odds ratio for each additional repeat was 9.07%. The authors hypothesized that the association of undermasculinized genitalia and isolated male factor infertility with AR(Gln)n length provided further evidence that they may represent different degrees of severity of the same disease process. </p><p>The fact that sperm numbers range from 20 to 300 million/mL in normal men without any indication of changed endocrine parameters led von Eckardstein et al. (2001) to assume that genetic variability of transduction of androgen signaling could be important. They compared the variable number of CAG repeats in the AR with sperm concentrations in men with normal ejaculate parameters (62 fathers and 69 volunteers participating in clinical trials). In multivariate analysis, CAG repeat length did not differ between the volunteers and the fathers, but was significantly correlated to sperm concentrations with a coefficient of -0.25. When compared with a group of infertile men, 14 with and 30 without a family history of infertility, no such correlation was found. The authors concluded that men with short CAG repeats have the highest sperm output within the normal fertile population, and that AR polymorphisms contribute to the efficiency of spermatogenesis in normal men, but do not play a predominant role in male infertility. </p><p>Zitzmann et al. (2001) investigated the interactions among the CAG polymorphism, serum levels of sex hormones, cardiovascular risk factors, and flow-mediated and nitrate-induced vasodilatation of the brachial artery in 110 healthy males aged 25 to 50 years. The number of CAG repeats had no significant correlations with serum concentrations of total or free testosterone. Stepwise multiple regression analysis revealed positive correlations of the number of CAG repeats with serum levels of high density lipoprotein (HDL) cholesterol and flow-mediated vasodilatation. The association of CAG repeats with HDL cholesterol was independent of body fat content and serum levels of free testosterone, both of which had significant negative correlations with HDL cholesterol. The authors concluded that a low number of CAG repeats in the AR gene implies a greater chance for low levels of HDL cholesterol and reduced endothelial response to ischemia, which are important risk factors for coronary heart disease. </p><p>Zitzmann et al. (2003) investigated the effect of AR CAG(n) repeat length on prostate volume and growth in testosterone-substituted hypogonadal men, 69 with primary hypogonadism and 62 with secondary hypogonadism. Average prostate size increased from 15.8 +/- 6.1 ml to 23.0 +/- 6.8 ml. ANOVA including covariates revealed initial prostate size to be dependent on age and baseline testosterone levels but not on number of (CAG)n. Prostate growth per year and absolute prostate size under substituted testosterone levels were strongly dependent on (CAG)n, with lower treatment effects in longer repeats. The odds ratio for men with fewer than 20 (CAG)n, compared with those with 20 or more (CAG)n, to develop a prostate size of at least 30 ml under testosterone substitution, was 8.7 (95% CI, 3.1-24.3; p less than 0.001). This observation was strongly age-dependent, with a more pronounced odds ratio in men older than 40 years. The authors concluded that this first pharmacogenetic study on androgen substitution in hypogonadal men demonstrated a marked influence of the AR gene (CAG)n polymorphism on prostate growth. </p><p>Zitzmann et al. (2004) analyzed phenotypic and clinical traits in 77 newly diagnosed and untreated patients with Klinefelter syndrome and a 47,XXY karyotype in regard to the putative influence of X chromosome inactivation and AR (CAG)n length. In 48 men who were hypogonadal and received T substitution therapy, pharmacogenetic effects were investigated. The shorter (CAG)n allele was preferentially inactive. (CAG)n length was positively associated with body height. Bone density and the relation of arm span to body height were inversely related to (CAG)n length. The presence of long (CAG)n was predictive for gynecomastia and smaller testes, whereas short (CAG)n were associated with a stable partnership and professions requiring higher standards of education also when corrected for family background. There was a trend for men with longer (CAG)n to be diagnosed earlier in life. Under testosterone substitution, men with shorter (CAG)n exhibited a more profound suppression of luteinizing hormone (LH; see 152780) levels, augmented prostate growth, and higher hemoglobin concentrations. The effects of testosterone substitution are pharmacogenetically modified, and this finding is magnified by preferential inactivation of the more functional short (CAG)n allele. </p><p>Zinn et al. (2005) investigated the role of the AR CAG(n) repeat length to phenotypic variability in Klinefelter syndrome. The CAG(n) repeat length was inversely correlated with penile length, a biologic indicator of early androgen action. Mosaicism, imprinting, and skewed X inactivation did not account for the variability of the Klinefelter syndrome phenotype. Zinn et al. (2005) concluded that normal genetic variation in the AR coding sequence may be clinically significant in the setting of early testicular failure and subnormal circulating testosterone levels, as occurs in Klinefelter syndrome. </p><p><strong><em>Association with Female-Specific Phenotypes</em></strong></p><p>
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Calvo et al. (2000) found no association between the AR CAG repeat number and hirsutism in women with or without hyperandrogenemia. Skewed X-chromosome inactivation was found in 10 (14.9%) of 67 subjects (3 with idiopathic hirsutism, 5 with hyperandrogenic hirsutism, and 2 controls; p = 0.746), which was not significant. </p><p>To investigate the role of the AR CAG repeat tract in polycystic ovarian syndrome (PCOS; 184700), Mifsud et al. (2000) measured its length in 91 patients with ultrasound diagnosis of polycystic ovaries, irregular menstrual cycles, and anovulatory infertility and compared them to 112 control subjects of proven fertility with regular menses. They compared differences in CAG length between patients whose serum testosterone levels were below the normal laboratory mean to those that were higher. There was a trend for a lower mean CAG biallelic length among anovulatory patients with serum testosterone less than 1.73 nmol/L compared with those whose testosterone was more than 1.73 nmol/L. This difference in CAG length between patients with low and high testosterone levels was highly significant when only the shorter allele of each individual was considered. Ethnic differences were also evident in the data; Indian subjects had a significantly shorter AR-CAG length compared with Chinese. The authors concluded that their data indicated an association between short CAG repeat length and the subset of anovulatory patients with low serum androgens, suggesting that the pathogenic mechanisms of polycystic ovaries in these patients could be due to the increased intrinsic androgenic activity associated with short AR alleles. </p><p>Hickey et al. (2002) compared frequency distribution of CAG repeat alleles and their pattern of expression via X-inactivation analysis among 83 fertile women and 122 infertile women with PCOS, all of Australian Caucasian ethnicity. A population comparison with 831 predominantly fertile Australian women was also used. Infertile women with PCOS exhibited a greater frequency of CAG alleles or biallelic means greater than 22 repeats compared with both the fertile control group (p less than 0.05) and the general population (p less than 0.01). Preferential expression of longer CAG repeat alleles was also observed in PCOS and correlated with increased serum T. The authors concluded that the AR (CAG)n gene locus and/or its differential methylation patterns influence the disease process leading to PCOS. </p><p>To elucidate the possible role of genetic variation in AR, ESR1 (133430), and ESR2 (601663) on serum androgen levels in premenopausal women, Westberg et al. (2001) studied the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ESR1 gene, and the CA repeat polymorphism of the ESR2 gene in a population-based cohort of 270 women. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH (see 152780), than women with longer CAG repeat sequences. The CA repeat of the ESR2 gene also was associated with androgen and sex steroid hormone-binding globulin (SHBG; 182205) levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ESR1 gene was not associated with the levels of any of the hormones measured. The authors concluded that serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ESR2 gene. </p><p>In a study of 255 Canadian women with breast cancer (114480) and 461 controls, Giguere et al. (2001) found that those with an AR CAG repeat length of 39 or less had a significantly decreased risk for disease development (odds ratio of 0.5) compared to women with CAG repeat lengths greater than 40. The association was stronger in postmenopausal women (odds ratio of 0.3). Giguere et al. (2001) concluded that short alleles of the CAG repeat were protective against breast cancer, and suggested that the protection was the consequence of increased response and sensitivity to androgens, which may inhibit the growth of breast cancer cells. </p><p>To test the hypothesis that risk for the development of precocious pubarche and subsequent features of ovarian hyperandrogenism might relate to genetic variation in androgen receptor sensitivity, Ibanez et al. (2003) compared CAG repeat number in Barcelona-Spanish girls who presented with precocious pubarche against Spanish controls and examined the relationship between CAG number and clinical-metabolic phenotypes of ovarian hyperandrogenism post menarche. Girls with precocious pubarche had shorter mean CAG number than controls (PP vs controls: mean, range: 21.3, 7-31 repeats vs 22.0, 15-32, p = 0.003) and greater proportion of short alleles of 20 repeats or less (37.0% vs 24.6%, p = 0.002). Among postmenarcheal girls with precocious pubarche, shorter CAG number was associated with higher 17-hydroxy-progesterone levels in response to a GNRH (152760) agonist, indicative of ovarian hyperandrogenism; higher testosterone levels, acne, and hirsutism scores; and more menstrual cycle irregularities. The authors concluded shorter AR gene CAG number, indicative of increased androgen sensitivity, increases risk for precocious pubarche and subsequent ovarian hyperandrogenism. </p><p>To assess whether abnormalities in AR function in both peripheral blood leukocytes (PBLs) and androgen target tissues are present in children with premature pubarche, Vottero et al. (2006) studied 25 girls with PP, 23 prepubertal children, and 20 girls with Tanner stage II pubertal development. In PBLs from PP patients, AR gene methylation was significantly lower (p less than 0.01) than that of prepubertal children and similar to that of girls with Tanner II stage pubertal development. A negative correlation between AR gene methylation in PBLs and the age of normal children was detected. The mean number of CAG repeats was lower in PP patients than in prepubertal and Tanner stage girls, although it was within the normal range for the general population in both groups. Vottero et al. (2006) concluded that the increased AR activity observed in PP patients, as indicated by the reduced AR gene methylation pattern, together with the presence of shorter CAG repeats, might lead to hypersensitivity of the hair follicles to steroid hormones and therefore to the premature development of pubic hair. </p><p>From a study of 330 women with PCOS and 289 controls, Shah et al. (2008) reported that a smaller biallelic mean of CAG repeats in the AR gene was associated with increased odds of PCOS. X-chromosome inactivation was not different comparing cases with controls; however, in the subset with nonrandom inactivation, the chromosome bearing the shorter CAG allele was preferentially active in PCOS women. </p><p>Chatterjee et al. (2009) investigated CAG repeat number in exon 1 of the AR gene in 78 Indian women with premature ovarian failure (POF; see 311360) and 90 controls and found that the mean CAG repeat length was significantly longer in women with POF than in controls (p less than 0.001). The 22 and 24 CAG repeat alleles were found at the highest frequency in patients (15.38% and 12.8%, respectively), although the 19 CAG repeat allele was observed at the highest frequency (12.2%) in controls. Chatterjee et al. (2009) suggested that CAG repeat length might be pathogenic for POF, at least in a subset of Indian women. </p><p><strong><em>Association with Osteoarthritis</em></strong></p><p>
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In a case-control cohort of 158 Greek patients with idiopathic osteoarthritis of the knees (see 165720) and 193 controls, Fytili et al. (2005) studied long (L) and short (S) alleles of the -1174(TA)n, 1092+3607(CA)n, and 172(CAG)n repeat polymorphisms of the ESR1, ESR2, and androgen receptor genes, respectively. When odds ratios were adjusted for various risk factors, it was observed that women with LL genotypes for ESR2 and AR genes showed significantly increased risk for the development of osteoarthritis (p = 0.002 and 0.001, respectively). </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Edwards et al. (1992) demonstrated that the distribution of the number of CAG repeats in exon 1 of the AR gene was lowest in African Americans, intermediate in non-Hispanic whites, and highest in Asians. The distribution of allele size was bimodal in African Americans, and only in African Americans was there a deviation from Hardy-Weinberg equilibrium. Irvine et al. (1995) studied the distribution of the CAG and GC microsatellite repeats in exon 1 of the AR gene in African Americans, non-Hispanic whites, and Asians (Japanese and Chinese), and confirmed the findings of Edwards et al. (1992). The frequency of prostate cancer (301120) in the 3 racial groups is inversely proportional to the length of the repeats. One of the critical functions of the product of the AR gene is to activate the expression of target genes. This transactivation activity resides in the N-terminal domain of the protein encoded in exon 1, which contains the polymorphic repeats. The smaller size of the CAG repeat is associated with a higher level of receptor transactivation function, thereby possibly resulting in a higher risk of prostate cancer. Irvine et al. (1995) noted that Schoenberg et al. (1994) had observed a somatic mutation resulting in a contraction of the CAG repeat from 24 to 18 in an adenocarcinoma of the prostate, and that the effects of the shorter allele were implicated in the development of the tumor. </p><p>In the French and German populations, Correa-Cerro et al. (1999) found no association between the risk of prostate cancer and alleles of the CAG and GGC repeats in the first exon of the AR gene. </p><p>Kittles et al. (2001) presented data on CAG and GGC allelic variation and linkage disequilibrium in 6 diverse populations from Africa, Asia, and North America. Populations of African descent possessed significantly shorter alleles for the 2 loci than non-African populations (p less than 0.0001). Allelic diversity for both markers was higher among African Americans than any other population, including indigenous Africans from Sierra Leone and Nigeria. Approximately 20% of CAG and GGC repeat variance was attributed to differences between populations. All non-African populations possessed the same common haplotype whereas the 3 populations of African descent possessed 3 divergent common haplotypes. Significant linkage disequilibrium was observed in the sample of healthy African Americans. </p><p>Mifsud et al. (2000) found that the average biallelic mean CAG length in Chinese subjects (patients and controls) was longer than for Indians, being 23.16 +/- 0.17 and 22.08 +/- 0.5, respectively (p = 0.035). The mean length of the short allele was also different between the 2 groups. </p><p>Davis-Dao et al. (2007) performed a metaanalysis of data from a total of 3,027 cases and 2,722 controls extracted from 33 independent studies of the relationship between AR CAG repeat lengths and male infertility. Publication dates ranged from 1997 to 2006. Estimates of the standardized mean difference (95% confidence interval) were 0.19 (0.09-0.29) for the 33 studies and 0.31 (0.14-0.47) for a subset of 13 studies that used more stringent case and control selection criteria. Thus, in both groups, cases had statistically significantly longer CAG repeat length than controls. Publication date appeared to be a significant source of variation between studies; while repeat lengths among controls were nearly constant, the average repeat length among cases declined during the interval 1999 to 2005. The authors suggested that this may be attributable to changing patterns of referral to infertility clinics during this period, with the introduction of new therapies leading men with a wider array of conditions to seek treatment. Davis-Dao et al. (2007) concluded that their metaanalysis provided support for an association between increased androgen receptor CAG length and idiopathic male infertility, suggesting that even subtle disruptions in the androgen axis may compromise male fertility. </p>
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<span class="mim-font">
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<strong>Evolution</strong>
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<p>McLean et al. (2011) identified molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. They confirmed 510 such deletions in humans, which fall almost exclusively in noncoding regions and are enriched near genes involved in steroid hormone signaling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human AR, a molecular change correlated with anatomic loss of androgen-dependent sensory vibrissae and penile spines in the human lineage. Another deletion removes a forebrain subventricular zone enhancer near the tumor suppressor gene 'growth arrest- and DNA damage-inducible, gamma' (GADD45G; 604949), a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionarily divergence. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<p><strong><em>Animal Model of Spinal and Bulbar Muscular Atrophy</em></strong></p><p>
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La Spada et al. (1998) attempted to model disease pathogenesis and repeat instability at the SBMA (313200) locus by creating transgenic mouse lines with yeast artificial chromosomes carrying CAG repeat expansions in the human AR gene. Transgenic mice with (CAG)45 alleles showed an approximately 10% rate of repeat length instability in transgene-positive progeny. The (CAG)45 repeat tract was significantly more unstable with maternal transmission and as the transmitting female aged. A segment of about 70 kb of the AR locus appeared to contain a cis-acting instability element. </p><p>Abel et al. (2001) created transgenic mice that developed many of the motor symptoms of SBMA and had a truncated, highly expanded AR gene driven by the neurofilament light chain (162280) promoter. In addition, transgenic mice created with the prion protein (176640) promoter developed widespread neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases. The distribution of neurologic symptoms depended on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or function. The transgenic mice that were generated developed neuronal intranuclear inclusions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. These inclusions were ubiquitinated and sequestered molecular chaperones, components of the 26S proteasome (604449) and the transcriptional activator CREB-binding protein (CBP; 600140). Apart from the presence of NIIs, evidence of neuropathology or neurogenic muscle atrophy was absent, suggesting to the authors that the neurologic phenotypes observed were the result of neuronal dysfunction rather than neuronal degeneration. Similar findings were reported by Adachi et al. (2001), who generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human AR promoter. The authors concluded that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration. </p><p>McManamny et al. (2002) developed a transgenic model of SBMA expressing a full-length human AR cDNA carrying 65 (AR-65) or 120 CAG repeats (AR-120), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR-120 transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR-120 mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, suggesting that the polyglutamine repeat expansion may cause a dominant gain-of-function mutation in AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. </p><p>Katsuno et al. (2002) found that the SBMA neurologic phenotype was markedly pronounced in male transgenic mice carrying an AR protein with 97 expanded CAG repeats compared to female mice. The phenotype in males was dramatically rescued by castration, and the few manifestations in the female mice were markedly worsened with testosterone administration. Testosterone in the uncastrated males and treated females was associated with increased translocation of the mutant AR into the nucleus, which was associated with a more severe phenotype. Katsuno et al. (2002) concluded that nuclear localization of mutant AR was important in inducing neuronal cell dysfunction and degeneration. </p><p>Using an N-terminal fragment of the human AR protein, Chan et al. (2002) studied SBMA in Drosophila. Expression of a pathogenic AR protein with an expanded polyglutamine repeat in Drosophila resulted in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. Flies with a compromised ubiquitin-proteasome pathway showed enhanced degeneration and decreased polyglutamine protein solubility, whereas overexpression of Hsp70 (see 140550) modulated neurodegeneration. The authors suggested that posttranslational protein modification, including the ubiquitin-proteasome and the UBL1 (601912) pathways, may modulate polyglutamine pathogenesis. </p><p>Takeyama et al. (2002) found that Drosophila eye photoreceptor neurons with targeted expression of an expanded AR protein showed increased neurodegeneration following ingestion of either androgen agonists or antagonists. Further protein studies indicated that ligand binding to the mutant expanded protein induced a structural alteration of the AR protein with nuclear translocation. </p><p>To study the cellular consequences of chronic low-level exposure to expanded polyglutamine proteins, Cowan et al. (2003) constructed mouse cell lines expressing either the full-length AR or truncated forms containing 25 or 65 glutamines. Expression of the polyglutamine-expanded truncated AR protein resulted in the formation of cytoplasmic and nuclear aggregates and eventual cell death. Nuclear aggregates preferentially stained positive for hsp72 (HSPA1A; 140550), a sensitive indicator of a cellular stress response. Biochemical studies revealed that the presence of nuclear aggregates correlated with activation of the c-jun N-terminal kinase (JNK; 601158). Different metabolic insults, including heat shock treatment, and exposure to sodium arsenite or menadione, proved more toxic to those cells expressing the polyglutamine-expanded truncated protein than to cells expressing the nonexpanded form. Once expressed, hsp72 failed to localize normally and instead was sequestered within the protein aggregates. The authors concluded that abnormal stress responses may contribute to enhanced cell vulnerability in cells expressing polyglutamine-expanded proteins and may increase the propensity of such cells to form cytoplasmic and nuclear inclusions. </p><p>Sopher et al. (2004) found that transgenic mice with a 100-CAG repeat in the AR gene (AR-100) developed a phenotype that was similar to SBMA. Pathologic examination showed AR-positive nuclear inclusions in CNS motor neurons, muscle, and liver, and diffuse AR staining in spinal cord motor neurons. Coimmunoprecipitation studies showed increased binding of Cbp by AR in a glutamine length-dependent fashion, suggesting that polyglutamine tracts may interfere with transcription. Oosthuyse et al. (2001) reported that deletion of a Cbp-regulated element in the Vegf gene (192240) produced an SBMA-like phenotype in mice. Using PCR and protein analysis, Sopher et al. (2004) found decreased expression of the Vegf164 isoform in AR-100 mice compared to controls. In vitro studies showed that Vegf164 supplementation and overexpression of Cbp independently rescued AR polyglutamine-induced cell death. Sopher et al. (2004) suggested that SBMA motor neuronopathy involves altered expression of VEGF, consistent with a role for VEGF as a neurotropic/survival factor in motor neuron disease. </p><p>Yu et al. (2006) found that transgenic mice with the 113-CAG repeat (AR113Q) in the AR gene demonstrated androgen-dependent neuromuscular weakness accompanied by myopathic and neuropathic morphologic changes in skeletal muscle, including atrophic, angulated fibers and internal nuclei. AR113Q mice exhibited androgen-dependent early death at 2 to 4 months of age; surgical castration completely prevented early death. Postmortem examination indicated that the mice died of acute urinary tract obstruction due to myopathic changes in the skeletal muscle of the lower urinary tract associated with myotonic discharges. Gene expression analysis of these muscles showed decreased expression of the Clcn1 (118425) and Scn4a (603967) genes. Hindlimb muscle showed similar myopathic features and decreased expression of Nt4 (162662) and Gdnf (600837). Yu et al. (2006) concluded that there is an important myopathic contribution to the pathogenesis of Kennedy disease. </p><p>Monks et al. (2007) found that transgenic mice overexpressing wildtype human AR exclusively in skeletal muscle displayed androgen-dependent muscle weakness and early death. Transgenic mice also showed changes in muscle morphology and gene expression consistent with neurogenic atrophy and exhibited motor axon loss. These features reproduced those seen in models of Kennedy disease. Monks et al. (2007) concluded that toxicity in skeletal muscle is sufficient to cause motoneuron disease and that overexpression of AR can exert toxicity comparable with that of the polyglutamine-expanded protein. </p><p>Montie et al. (2009) genetically manipulated the nuclear localization signal of polyglutamine-expanded AR. Transgenic mice expressing this mutant AR displayed inefficient nuclear translocation and substantially improved motor function compared with Sbma mice. Analysis of cell models of SBMA indicated that nuclear localization of polyglutamine-expanded AR was necessary but not sufficient for aggregation and toxicity and that androgen binding by AR was required for these disease features. Studies of cultured motor neurons showed that the autophagic pathway was able to degrade cytoplasmically retained polyglutamine-expanded AR and represented an endogenous neuroprotective mechanism. Pharmacologic induction of autophagy rescued motor neurons from the toxic effects of even nuclear-residing mutant AR, suggesting a therapeutic role for autophagy in this nucleus-centric disease. Montie et al. (2009) concluded that polyglutamine-expanded AR must reside within nuclei in the presence of its ligand to cause SBMA. </p><p>In Drosophila, Nedelsky et al. (2010) demonstrated that expression of expanded AR-52Q underwent ligand-dependent nuclear localization in the eye and caused neurodegeneration associated with puncta. Similar systemic neurodegeneration occurred when the mutant gene was expressed in larvae. Studies using mutant constructs lacking certain domains indicated that nuclear translocation of polyQ-expanded AR was necessary, but not sufficient, for toxicity. The protein needed an intact DNA-binding domain for toxicity, suggesting that the normal function of AR as a transcription factor plays a role in pathogenesis. Studies using RNAi-mediated knockdown of downstream AR coregulators and select mutant analysis indicated that a functional AF-2 binding domain was required for toxicity. Importantly, overexpression of wildtype AR showed a similar, yet milder, degenerative phenotype, suggesting that high levels of normal AR activity can cause degeneration even in the absence of polyQ expansion. Nedelsky et al. (2010) concluded that SBMA pathogenesis is mediated by amplification of native AR interactions and that polyQ-mediated enhanced AR toxicity requires DNA binding followed by association with AF-2 coregulators. </p><p><strong><em>Animal Models of Other Diseases</em></strong></p><p>
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In the 'transgenic adenocarcinoma of the mouse prostate' (TRAMP) model, expression of the transgene is initially regulated by androgens and restricted to the prostate epithelial cells of the dorsolateral and ventral lobes (Gingrich and Greenberg, 1996; Gingrich et al., 1997). Spontaneous prostate tumors that histologically resemble the human disease arise with a short latency period and exhibit progression from prostatic intraepithelial neoplasia to severe hyperplasia and adenocarcinoma. Buchanan et al. (2001) presented the first report of a spontaneous AR gene mutation in the TRAMP mouse and the colocation of this mutation with somatic AR gene mutations identified in human prostate tumors to amino acids 668-671 (QPIF), at the boundary of the hinge and ligand-binding domains. These mutations resulted in AR variants with 2- to 4-fold increased transactivation capacity in response to dihydrotestosterone (DHT) and other nonclassical ligands compared with wildtype AR. Mutations in this region had no apparent effect on receptor levels, ligand-binding kinetics, or DNA binding. The authors concluded that expression of these or similar variants could explain the emergence of hormone-refractory disease in a subset of patients. </p><p>Yeh et al. (2002) reported the use of a Cre/lox conditional knockout strategy to generate AR knockout mice. Phenotype analysis showed that the AR knockout male mice had a female-like appearance and body weight. Their testes were 80% smaller and serum testosterone concentrations were lower than the wildtype mice. Spermatogenesis was arrested at pachytene spermatocytes. The number and size of adipocytes were also different between the wildtype and AR knockout mice. Cancellous bone volumes of AR knockout male mice were reduced compared with wildtype littermates. The average number of pups per litter in homozygous and heterozygous AR knockout female mice was lower than in wildtype female mice, suggesting potential defects in female fertility and/or ovulation. The model could be useful for studying androgen functions in the selective androgen target tissues in female or male mice. </p><p>Sato et al. (2003) found the male Ar knockout (KO) mice exhibited typical features of testicular feminization in external reproductive organs with growth retardation. The growth curve of male Ar KO mice was similar to that of wildtype female littermates until the tenth week of age, but thereafter mutant males developed obesity. A clear increase in wet weights of white adipose tissues, but not brown adipose tissues, was evident in 30-week-old male Ar KO mice. There was no significant effect of Ar KO on serum lipid parameters or food intake. No accumulation of lipids was found in adipocytes of female homozygous Ar KO mice. Sato et al. (2003) concluded that AR may serve as a negative regulator of adipose development in adult males. </p><p>Ikeda et al. (2005) found that Ar KO male mice with or without angiotensin II (see 106150) stimulation showed a significant reduction in heart-to-body weight ratio compared with wildtype male mice. Echocardiographic analysis demonstrated impaired concentric hypertrophic response and left ventricular function in angiotensin II-stimulated Ar KO mice, and Western blot analysis showed that Ar KO mice had reduced angiotensin II-induced Erk signaling (see MAPK3; 601795). Furthermore, angiotensin II stimulation caused elevated cardiac fibrosis and enhanced expression of fibrosis-related genes in Ar KO mice compared with wildtype mice. Ikeda et al. (2005) concluded that the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during hypertrophic stress. </p><p>Han et al. (2005) found that transgenic mice expressing an Ar E231G mutation, corresponding to human E251G, showed rapid development of prostatic intraepithelial neoplasia that progressed to invasive and metastatic cancer. The E231G mutation occurs in a highly conserved signature motif of the N-terminal domain that influences interactions with other cellular coregulators. Significant pathologic changes were not observed in transgenic mice overexpressing wildtype Ar or the T857A mutation, corresponding to human T877A (313700.0027). The findings indicated that the E231G mutation induces deregulated growth and that, in some cases, AR may act as an oncogene. </p><p>Shiina et al. (2006) observed that female Ar-null mice appeared normal but developed premature ovarian failure (see 311360) with aberrant ovarian gene expression. Eight-week-old Ar -/- females were fertile, but had lower follicle numbers and impaired mammary development, and produced only half of the normal number of pups per litter. Forty-week-old Ar -/- females were infertile due to complete loss of follicles. Genomewide microarray analysis of mRNA from Ar -/- ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by Ar. Shiina et al. (2006) suggested that AR function is required for normal female reproduction, particularly folliculogenesis. </p><p>Prostate cancer may become resistant to treatment with androgen deprivation therapy (ADT). Niu et al. (2008) demonstrated that the prostate AR may function as both a suppressor and a proliferator of prostate cancer metastasis, depending on its tissue location. Coculture of human stromal prostate WPMY1 cells with human AR-null epithelial prostate cancer PC3 cells showed that AR-knockdown in WPMY1 cells or restoration of AR in PC3 cells suppressed prostate cancer metastasis. Furthermore, in bone lesion assays and in vivo mouse models of prostate cancer, restoration of the AR in PC3 epithelial cells resulted in decreased tumor invasion. Knockdown of the AR in epithelial ADT-resistant prostate cancer cells resulted in increased cell invasion in vitro and in vivo. Transgenic mice lacking the prostate epithelial AR showed increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells, which coincided with larger and more invasive metastatic tumors and earlier death compared to wildtype mice. An evaluation of human prostate tumors showed a significant difference in AR expression between primary (91.75%) and metastatic (67.86%) prostate tumors. Together, these results indicated that AR functions in epithelial cells as a tumor suppressor of prostate cancer metastasis, whereas AR acts in stromal cells as a stimulator of prostate cancer progression. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>60 Selected Examples):</strong>
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<h4>
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<span class="mim-font">
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<strong>.0001 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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</span>
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</h4>
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AR, PARTIAL DEL
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ClinVar: RCV000010476
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<p>Brown et al. (1988) used cDNA probes in the study of patients from 6 unrelated families with complete androgen insensitivity syndrome (300068) of the receptor-negative type. The Southern blot pattern was normal in 5 of the 6 patients; in 1 patient a partial deletion of the androgen-receptor gene involving the steroid-binding domain was detected. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 ANDROGEN INSENSITIVITY, COMPLETE</strong>
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</span>
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</h4>
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AR, PARTIAL DEL
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ClinVar: RCV000010477
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<p>Pinsky et al. (1989) and Trifiro et al. (1989) reported a patient with complete androgen insensitivity syndrome (300068) and a deletion in the AR gene different from that reported by Brown et al. (1988). The patient also had mental retardation, which may reflect a contiguous gene syndrome; however, no evidence of deletion other than in the AR gene could be obtained by hybridization with 11 additional single-copy probes from Xq11-q13. </p>
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</span>
|
|
</div>
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG773CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852562,
|
|
|
|
|
|
|
|
ClinVar: RCV000010478, RCV001056795, RCV001818149
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with complete androgen insensitivity syndrome (300068), Trifiro et al. (1989) identified a CGC-to-TGC change in exon 6 of the AR gene that resulted in an arg773-to-cys substitution. Position 773 of the androgen receptor is in 1 of 4 regions of its androgen binding domain that are homologous to corresponding regions in the steroid-binding domains of 3 other members of the steroid receptor subfamily that includes those for progesterone, glucocorticoid, and mineralocorticoid.</p>
|
|
</span>
|
|
</div>
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, TRP717TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852563,
|
|
|
|
|
|
gnomAD: rs137852563,
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|
|
|
|
|
ClinVar: RCV000010479
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of complete androgen insensitivity (300068), Sai et al. (1990) demonstrated a guanine-to-adenine transition at nucleotide 2682 of the AR gene, changing codon 717 from tryptophan to a translation stop signal. Codon 717 is in exon 4; thus the mutation predicted synthesis of a truncated receptor that lacked most of its androgen-binding domain. The substitution abolished a recognition sequence for HaeIII. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, VAL866MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852564,
|
|
|
|
|
|
|
|
ClinVar: RCV000010480, RCV000763628, RCV001381188, RCV003421916
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of sibs with complete androgen insensitivity (300068) and reduced AR binding capacity for dihydrotestosterone, Lubahn et al. (1989) found that the AR steroid-binding domain (exon G) contained a single guanine-to-adenine mutation, resulting in replacement of valine with methionine at amino acid residue 866. As expected, the carrier mother had both normal and mutant AR genes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, TRP794TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852565,
|
|
|
|
|
|
gnomAD: rs137852565,
|
|
|
|
|
|
ClinVar: RCV000010481, RCV000698414
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 9 patients with androgen resistance (300068) and absent dihydrotestosterone binding in cultured fibroblasts, Marcelli et al. (1990) found a change of tryptophan-794 to a stop codon (TGG to TGA) in the AR gene. S(1) nuclease protection assays showed that normal levels of AR mRNA were present in skin fibroblasts of this patient. Transfection of a mutated androgen receptor cDNA containing a termination codon at position 794 into eukaryotic cells resulted in formation of a normal amount of receptor protein, but the expressed protein did not bind dihydrotestosterone. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, LYS588TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852566,
|
|
|
|
|
|
|
|
ClinVar: RCV000010482
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with complete androgen resistance (300068), Marcelli et al. (1990) found a thymine-for-adenine substitution at nucleotide position 1924 in the AR gene, converting the AAA codon 588 (lysine) into a premature termination codon (TAA). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, TYR761CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852567,
|
|
|
|
|
|
|
|
ClinVar: RCV000010484
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Grino et al. (1989) described a family in which partial androgen resistance (312300) was associated with profound hypospadias but considerable virilization after the time of expected puberty. The androgen receptor expressed in cultured skin fibroblasts from an affected member of this pedigree was normal in amount and exhibited only mild qualitative abnormalities. The functional defect could be largely overcome by high-dose androgen therapy. The clinical features were those of the Reifenstein syndrome. McPhaul et al. (1991) showed that the AR gene in this family contained 2 structural alterations: an A-to-G change at position 2444 in exon 5 that converted tyrosine-761 to cysteine, and a shortened glutamine homopolymeric segment in exon 1 that encoded 12 rather than the usual 20 to 22 glutamines. McPhaul et al. (1991) demonstrated that the presence of the cysteine residue at position 761 caused a rapid dissociation of dihydrotestosterone from the receptor protein. Marked thermolability of the receptor protein was demonstrable only upon introduction of partial deletion of the glutamine homopolymeric segment in addition to the cysteine substitution. The phenotype in this family shows the characteristics referred to as Reifenstein syndrome. </p><p>Murono et al. (1995) found this mutation in an individual with androgen sensitivity with ambiguous genitalia; they referred to the mutation as TYR763CYS. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, LYS882TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852568,
|
|
|
|
|
|
|
|
ClinVar: RCV000010485
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with complete androgen insensitivity (300068), Trifiro et al. (1991) found an adenine-to-thymine transversion in exon 8 of the AR gene that changed the sense of codon 882 from lysine to an amber (UAG) translation termination signal. (See 141900.0312 for the origin of the designation 'amber.' See 219700.0030 for an example of the ochre (UAA) type of translation termination signal.) </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG772CYS
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000010478, RCV001056795, RCV001818149
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the receptor-negative form of complete testicular feminization (300068), Marcelli et al. (1991) found a single substitution (CGC to TGC) at nucleotide 2476 of the AR gene. This alteration resulted in the conversion of an arginine to a cysteine at amino acid 772. Both a decrease in AR mRNA and impairment of the receptor molecule resulted. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ALA771THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852569,
|
|
|
|
|
|
|
|
ClinVar: RCV000010487, RCV000640478, RCV001269612
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated families, Klocker et al. (1992) demonstrated that the Reifenstein syndrome (312300) was due to a G-to-A transition at nucleotide 2314 of the AR gene, which changed the alanine codon (GCC) immediately after the first cysteine of the second zinc finger motif of the androgen receptor into a threonine codon (ACC). The 5 patients in the 2 families presented with perineoscrotal hypospadias and undescended testes. After puberty they showed small testes, no palpable prostate, micropenis, azoospermia, and gynecomastia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, MET786VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852570,
|
|
|
|
|
|
|
|
ClinVar: RCV000010488
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Japanese sibs with complete androgen insensitivity (300068) and undetectable androgen binding in cultured pubic skin fibroblasts, Nakao et al. (1992) demonstrated a single nucleotide substitution in exon F of the AR gene, resulting in a methionine-to-valine (A-to-G) change at position 786 within the steroid-binding domain of AR. Although reconstruction of this mutation by site-directed mutagenesis into human AR cDNA followed by expression in COS-1 cells led to production of a normal amount and molecular mass of immunodetectable AR protein, the mutant AR showed markedly low affinity of androgen binding. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PROSTATE CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, VAL730MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852571,
|
|
|
|
|
|
gnomAD: rs137852571,
|
|
|
|
|
|
ClinVar: RCV000010491, RCV002247310, RCV003764544
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 26 specimens of untreated organ-confined stage B prostate cancer, Newmark et al. (1992) found a somatic AR mutation by study of genomic DNA by PCR followed by denaturing gradient gel electrophoresis (DGGE); see HPCX3 (301120). Sequencing revealed a G-to-A transition in exon E, changing valine to methionine at codon 730. An abundance of the mutated fragment indicated its presence in cells with a growth advantage. The mutation was not detectable in peripheral blood lymphocyte DNA. They postulated that somatic mutation in the AR gene leading to persistent expression could give rise to androgen-independent prostate cancer. Mutation occurred in the hormone-binding domain in a region highly conserved among all steroid receptors. Newmark et al. (1992) pointed to a possibly comparable situation with an estrogen receptor mRNA variant found in breast cancer that lacked part of the hormone-binding domain; it yielded a mutant receptor that was constitutively active in the absence of estrogen, providing a potential mechanism for estrogen-independent breast cancer growth (McGuire et al., 1991). </p><p>Overexpression of amplified genes is often associated with the acquisition of resistance to cancer therapeutic agents in vitro. Visakorpi et al. (1995) identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer that involved amplification of the androgen receptor gene. They found high-level AR amplification in 7 of 23 (30%) recurrent tumors, but in none of the specimens taken from the same patients prior to therapy. Results suggested that AR amplification emerges during androgen deprivation therapy by facilitating tumor cell growth in low androgen concentrations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, (CAG)n REPEAT EXPANSION
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs3032358,
|
|
|
|
|
|
gnomAD: rs3032358,
|
|
|
|
|
|
ClinVar: RCV000010492
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 35 unrelated patients with spinal and bulbar muscular atrophy (313200), La Spada et al. (1991) found an increased size of a polymorphic tandem CAG repeat (polyglutamine tract) in the coding region of the androgen receptor gene. These amplified repeats were found in none of 75 controls and segregated with the disease in 15 families. The association was not likely to be due to linkage disequilibrium because 11 different disease alleles were observed. </p><p>Lund et al. (2001) haplotyped 123 Kennedy disease families from Finland, Sweden, Norway, Denmark, Germany, Belgium, Italy, Japan, Australia, and Canada. The haplotype analysis showed different founder haplotypes around the world, implying that the CAG repeat expansion mutation in Kennedy disease is not a unique event. No particular expansion-prone haplotype could be detected. Among 95 Kennedy disease patients with defined ages at onset, the authors found a weak negative correlation between the CAG repeat length and the age of onset. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG773HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852572,
|
|
|
|
|
|
|
|
ClinVar: RCV000010493, RCV001384255, RCV001781214
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Whereas a C-to-T transition in codon 773 changes arginine to cysteine (313700.0003) and results in complete androgen insensitivity (300068), a G-to-A transition changes amino acid 773 to histidine and also results in complete androgen insensitivity (Prior et al., 1992). The finding is consistent with the evolutionary preservation of the position homologous to arg773 in the androgen receptor. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 ANDROGEN INSENSITIVITY, PARTIAL, WITH OR WITHOUT BREAST CANCER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG607GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852573,
|
|
|
|
|
|
|
|
ClinVar: RCV000010494, RCV000382955, RCV000806067
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In brothers with penoscrotal hypospadias who developed infiltrating ductal cancers of the breast at ages 75 and 55 years, respectively, Wooster et al. (1992) identified a G-to-A transition in exon 3 of the androgen receptor resulting in an arg607-to-gln (R607Q) substitution. Arg607, which is located within the second zinc finger, is conserved in the androgen, estrogen, glucocorticoid, and mineralocorticoid receptors. </p><p>Weidemann et al. (1998) found the same mutation in an individual with partial androgen insensitivity. At 19 years of age, the patient had undervirilization and endocrine findings typical for androgen insensitivity. In an attempt to improve virilization, high-dose testosterone enanthate treatment (250 mg once a week by intramuscular injection) was begun. After 3.5 years of this treatment, marked promotion of virilization was achieved, i.e., lowering of voice, male pattern secondary hair distribution, marked growth of beard and coarse body hair, increase in phallic size, increase in bone mineral density, and decrease in mammary gland size. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, VAL865MET
|
|
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|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000010480, RCV000763628, RCV001381188, RCV003421916
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with complete androgen insensitivity (300068), Kazemi-Esfarjani et al. (1993) identified a G-to-A transition in exon 7 of the androgen receptor which converted codon 865 from GTG (val) to ATG (met). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, VAL865LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852564,
|
|
|
|
|
|
|
|
ClinVar: RCV000010496
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with partial androgen insensitivity (312300), Kazemi-Esfarjani et al. (1993) identified a G-to-T transversion in exon 7 of the androgen receptor which converted codon 865 from GTG (val) to TTG (leu). It was remarkable that a methionine substitution of this same codon (313700.0017) resulted in complete androgen insensitivity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG855HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs9332971,
|
|
|
|
|
|
|
|
ClinVar: RCV000010497, RCV000532628, RCV000582251, RCV003982834
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Kuwaiti brothers, born to nonconsanguineous parents, who presented in the neonatal period with severe perineal hypospadias, bilateral cryptorchidism, and micropenis, Batch et al. (1993) found a G-to-A transition in exon G of the AR gene, which caused an arg-to-his substitution at amino acid 855. The 2 boys had 46,XY karyotypes and showed normal testosterone biosynthesis and metabolism. Both showed a qualitative defect in androgen binding (see 312300), suggesting that the androgen receptor was defective. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 HYPOSPADIAS 1, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ILE869MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852574,
|
|
|
|
|
|
|
|
ClinVar: RCV000010498
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers, born to nonconsanguineous parents, who presented at birth with perineal hypospadias (HYSP1; 300633), Batch et al. (1993) found an A-to-C change in exon 2 of the AR gene, which caused an ile-to-met change at amino acid 869. Both brothers had a 46,XY karyotype, and endocrine investigations were normal in both. Both showed a qualitative defect in androgen binding, suggesting that the androgen receptor was defective. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, GLN60TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852575,
|
|
|
|
|
|
|
|
ClinVar: RCV000010499, RCV003129750
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 46,XY sibs with complete testicular feminization (300068) and a diminished amount of qualitatively abnormal AR, Zoppi et al. (1993) found a CAG-to-TAG change at nucleotide 340 in exon 1, which caused a gln-to-ter mutation at amino acid 60 in the AR gene. In vitro mutagenesis studies suggested the synthesis of the mutant AR is initiated downstream of the termination codon at reduced levels and that each molecule is functionally impaired. These results defined a novel mechanism causing androgen resistance: the combination of decreased amount and functional impairment of AR caused by an abnormality within the amino terminus of the receptor. Zoppi et al. (1993) determined that the mutation was not present in a 46,XY fetal sib of the proband at 9 weeks' gestation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, 5-KB DEL, EX E
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000010500
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with complete androgen insensitivity (300068), MacLean et al. (1993) found 2 different deletions in the AR gene. Two affected sisters and their heterozygous mother, aunt, and grandmother had a 5-kb deletion of exon E and surrounding introns. An affected (XY) aunt had a 5-kb deletion of exons F and G and surrounding intronic sequences (313700.0023). Both deletions had 1 breakpoint in the same 200-bp region of intron 5, but they extended in opposite directions. Both deletions would alter the reading frame of the downstream exons, resulting in the production of abnormal receptors that lack vital parts of the steroid binding domain. The inability of the receptor to bind ligand would thus render the target tissues unresponsive to androgens. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, 5-KB DEL, EX F,G
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000010501
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 313700.0022 and MacLean et al. (1993). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 ANDROGEN INSENSITIVITY, PARTIAL, WITH BREAST CANCER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG608LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852576,
|
|
|
|
|
|
|
|
ClinVar: RCV000010502
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 13 cases of male breast cancer, Lobaccaro et al. (1993) found by single-strand conformation polymorphism and direct sequencing a G-to-A transition at nucleotide 2185 that changed arginine-608 into lysine in a highly conserved region of the second zinc finger of the androgen receptor. The patient was a 38-year-old man with partial androgen insensitivity and normal androgen-binding capacity in cultured genital skin fibroblasts. The authors noted the previously reported arg607-to-gln mutation (313700.0016). They concluded that the genetic abnormality was not fortuitous. A decrease in androgen action within breast cells could account for the development of male breast cancer by the loss of a protective effect of androgens on these cells. Activation of estrogen-regulated genes by change in the DNA-binding characteristics of the mutant androgen receptor could not, however, be ruled out. The patient in this case had markedly ambiguous genitalia (micropenis, hypospadias, and bifid scrotum) associated with bilateral gynecomastia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG839HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs9332969,
|
|
|
|
|
|
gnomAD: rs9332969,
|
|
|
|
|
|
ClinVar: RCV000010503, RCV000582333, RCV000814875, RCV001269861
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Beitel et al. (1994) described an arg839-to-his mutation in affected members of 2 families in whom external genitalia were predominantly female at birth and sex-of-rearing had been female. In a third family, the external genitalia of affected members were predominantly male at birth, and sex-of-rearing had been male; however, these individuals carried an arg839-to-cys mutation (313700.0026). In genital skin fibroblasts, both mutant receptors had a normal androgen-binding capacity, but they differed in selected indices of affinity for dihydrotestosterone or 2 synthetic androgens. In transiently cotransfected androgen-treated COS-1 cells, both mutant receptors transactivated a reporter gene subnormally. The his839 mutant was less active than its partner, primarily because its androgen-binding activity was more unstable during prolonged exposure to androgen (see 312300). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG839CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852577,
|
|
|
|
|
|
|
|
ClinVar: RCV000010504, RCV000010529, RCV000640474, RCV001269809
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 313700.0025 Beitel et al. (1994). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 PROSTATE CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, THR877ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852578,
|
|
|
|
|
|
|
|
ClinVar: RCV000010505, RCV004668712
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 of 24 specimens of prostatic tissue derived from transurethral resections in patients with metastatic prostate cancer, Gaddipati et al. (1994) found a thr877-to-ala mutation in the hormone-binding domain of the AR gene; see HPCX3 (301120). The same mutation had been reported previously in a metastatic prostatic cancer cell line where it conferred on the androgen receptor an altered ligand-binding specificity that was stimulated by estrogens, progestagens, and antiandrogens. Gaddipati et al. (1994) suggested that the codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. The stimulatory effect of the usual therapeutic agents on the codon 877 mutant AR may contribute to treatment-refractory disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, LEU676PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852579,
|
|
|
|
|
|
|
|
ClinVar: RCV000010506
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large Manitoba Hutterite kindred with X-linked receptor-negative complete androgen insensitivity (300068), Belsham et al. (1995) found a T-to-C transition in exon 4 in the AR gene that resulted in replacement of leucine-676 with proline at a site that is conserved in numerous members of the steroid receptor gene family. The mutation at nucleotide 2558 was found to abolish receptor binding activity when the mutant AR was transfected into COS-1 cells. The mutation was detected by MspI digestion of the PCR-amplified exon 4 product. The propositus and 3 maternal aunts had the complete syndrome. The Manitoba Hutterites are Schmiedeleut and evolved from a relatively small founder population that consisted of a maximum of 124 ancestral genomes (Lewis et al., 1985). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 PROSTATE CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, THR877SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852580,
|
|
|
|
|
|
|
|
ClinVar: RCV000010507
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Most metastatic androgen-independent prostate cancers express high levels of androgen-receptor gene transcripts. Taplin et al. (1995) identified point mutations in the AR gene in metastatic cells from 5 of 10 patients with prostate cancers in this category (HPCX3; 301120). One mutation, thr877-to-ser, was in the same codon as that found previously in the androgen-independent prostate cancer cell line (313700.0027). In 2 of the 5 patients, the mutations were not detected in the primary tumors. Functional studies of 2 of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen. Four different mutations in the AR gene were identified in 1 tumor (313700.0033). </p><p>Wilson (1995) used the expression 'promiscuous receptor' to refer to the mutant receptor that, although losing its specificity for androgen, gains the ability to respond to hormones (estradiol and progesterone) that it would not ordinarily recognize. Under these circumstances, other hormones can play the part ordinarily reserved for androgen. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 PROSTATE CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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AR, HIS874TYR
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|
<br />
|
|
|
|
SNP: rs137852581,
|
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|
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|
|
ClinVar: RCV000010508
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Taplin et al. (1995) found a CAT-to-TAT transition in the AR gene in metastatic cells of prostate cancer in 1 out of 10 patients studied. The nucleotide substitution resulted in a his874-to-tyr amino acid change. See HPCX3 (301120). </p>
|
|
</span>
|
|
</div>
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|
<div>
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|
<br />
|
|
</div>
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|
</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 PROSTATE CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
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|
AR, GLN902ARG
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|
<br />
|
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|
|
SNP: rs137852582,
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|
|
ClinVar: RCV000010509
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Taplin et al. (1995) found a CAA-to-CGA transition in the AR gene in metastatic cells of prostate cancer in 1 out of 10 patients studied. The nucleotide substitution resulted in a gln902-to-arg amino acid change. See HPCX3 (301120). </p>
|
|
</span>
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|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 PROSTATE CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
AR, ALA721THR
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|
<br />
|
|
|
|
SNP: rs137852583,
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|
|
ClinVar: RCV000010510, RCV001305872, RCV004767001
|
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|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Taplin et al. (1995) found a GCC-to-ACC transition in the AR gene in metastatic cells of prostate cancer in 1 out of 10 patients studied. The nucleotide substitution led to an ala721-to-thr amino acid change. See HPCX3 (301120). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 PROSTATE CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, SER647ASN
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs137852584,
|
|
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|
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|
|
|
ClinVar: RCV000010483
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of metastatic androgen-independent prostate cancer (HPCX3; 301120), Taplin et al. (1995) found that 100% of metastatic cells carried an AR gene with 4 mutations resulting in the following amino acid substitutions: ser647-to-asn, gly724-to-asp, leu880-to-gln, and ala896-to-thr. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, LEU707ARG
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs137852585,
|
|
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|
|
|
ClinVar: RCV000010511
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lumbroso et al. (1996) investigated the molecular basis of androgen resistance in a female newborn with complete testicular feminization (300068). Sequencing of the AR gene identified a point mutation in exon 4 responsible for a leucine (CTG)-to-arginine (CGG) replacement at codon 707. This mutation resides in the amino-terminal part of the ligand-binding domain of the AR. In vitro studies showed that the mutant AR was functionally deficient as an androgen-binding molecule. Further, its binding to DNA was reduced and it was unable to induce transcriptional activation of an androgen-responsive reporter gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, CYS579PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852586,
|
|
|
|
|
|
|
|
ClinVar: RCV000010512
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of complete androgen insensitivity (300068), Imasaki et al. (1996) identified a TGC-to-TTC transversion, changing codon 579 of the AR gene from cys to phe. The mutation occurred in exon B encoding the first zinc finger of the DNA-binding domain of the AR gene. The patient was of the 'receptor-positive type,' i.e., the binding ability of the androgen receptor was normal both quantitatively and qualitatively. The nucleotide and amino acid numeration according to the sequence of Lubahn et al. (1988) was used to indicate the position of the specific amino acid codon. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, PHE582TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852587,
|
|
|
|
|
|
|
|
ClinVar: RCV000010513
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of complete androgen insensitivity syndrome (300068), Imasaki et al. (1996) identified a TTC-to-TAC transversion in the AR gene, changing codon 582 of the AR gene from phe to tyr. The mutation occurred in exon B encoding the first zinc finger of the DNA-binding domain of the AR gene. The patient was of the 'receptor-positive type,' i.e., the binding ability of the androgen receptor was normal both quantitatively and qualitatively. The nucleotide and amino acid numeration according to the sequence of Lubahn et al. (1988) was used to indicate the position of the specific amino acid codon. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 HYPOSPADIAS 1, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, PRO546SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852588,
|
|
|
|
|
|
|
|
ClinVar: RCV000010514, RCV004700212
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Sutherland et al. (1996) analyzed penile tissue from 40 patients who underwent reconstructive surgery for various degrees of hypospadias and found a C-to-T transition in exon 2 of the androgen receptor gene (pro546 to ser) in only 1 patient. The tissue was analyzed by single-strand conformation polymorphism in exons 2 to 8, followed by DNA sequencing if a possible mutation was found. In the child with the mutation, the distal shaft hypospadias (300633) was not associated with other genitourinary anomalies. No other patients had an identifiable mutation in the coding sequences of the exons tested. Of the 26 patients of whom adequate information was obtained, none had an affected father or brother. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, GLU2LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894742,
|
|
|
|
|
|
|
|
ClinVar: RCV000010515
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>With few exceptions, mutations in the human AR gene associated with androgen insensitivity have been limited to the DNA and steroid binding domains. Choong et al. (1996) characterized the novel molecular mechanism for AIS resulting from a G-to-A transition at codon 2 adjacent to the translation initiation codon in the N-terminal domain of the AR gene in 3 related individuals with partial androgen insensitivity syndrome (312300). They stated that this was the first report of a naturally occurring mutation that altered the nucleotide context of the ATG initiation codon at the critical G+4 residue, resulting in reduced translation efficiency. The family pedigree showed 5 affected individuals in 3 generations connected through carrier females in a characteristic X-linked inheritance pattern. The phenotype was that of ambiguous genitalia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 ANDROGEN INSENSITIVITY, COMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, MET780ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852589,
|
|
|
|
|
|
gnomAD: rs137852589,
|
|
|
|
|
|
ClinVar: RCV000010516
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of complete androgen insensitivity (300068), Jakubiczka et al. (1997) identified a met780-to-ile (M780I) missense mutation in the androgen receptor (AR) gene, which resulted from a G-to-T transversion converting ATG to ATT. It is puzzling that Batch et al. (1992) described a patient with the same amino acid substitution but the phenotype of partial androgen insensitivity. Jakubiczka et al. (1997) suggested that differences in the CAG repeat in exon A may be responsible for the differences in clinical consequences of the M780I mutation. </p><p>Mutations in the AR gene cause a wide spectrum of androgen insensitivity syndromes. Indeed, patients with the same missense mutation can have strongly divergent phenotypes, suggesting the influence of modifying factors. The polymorphic CAG repeat in the first exon of the AR gene may be such a modifying factor. Knoke et al. (1999) studied the influence of the length of the CAG repeat on the transactivation function of the M780I mutant AR, which can cause either partial or complete androgen insensitivity syndrome. The studies were done by cotransfection of HeLa cells with various CAG-AR expression vectors and a highly androgen-responsive luciferase reporter gene construct. In contrast to the wildtype AR, the transcriptional activity of the M780I mutant AR could be considerably enhanced by nonphysiologically high androgen concentrations. Furthermore, an inverse relationship between the number of the CAG repeats in the mutant AR and its activity was observed. </p><p>Boehmer et al. (2001) referred to this mutation as MET771ILE. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ARG846HIS
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000010497, RCV000532628, RCV000582251, RCV003982834
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Boehmer et al. (1997) described an arg846-to-his (R846H) mutation in the AR gene in 2 sibs with partial androgen insensitivity (312300). The mother had one AR allele with 14 CAGs and the other AR allele with 21 CAGs. Both affected brothers had the allele with 14 CAGs. Surprisingly, an unaffected brother also had inherited the AR allele with 14 CAGs, but without the mutation. This segregation pattern indicated that a germline mosaicism was present in the mother. Somatic mosaicism was also demonstrated in the mother; the mother's DNA hybridized with both a normal probe and the R846H probe. The intensity of the hybridization signal of the R846H versus the normal allele suggested that the amount of the mutant R846H allele was less than 10% of the normal allele in peripheral lymphocytes. </p><p>Boehmer et al. (2001) reported 2 46,XY sibs, children of first-cousin parents, with partial AIS who shared the R846H mutation, but had very different phenotypes. One sib with grade 5 AIS was raised as a girl; the other sib with grade 3 AIS was raised as a boy. In both sibs serum levels of hormones were measured; a sex hormone-binding globulin (SHBG; 182205) suppression test was completed; and mutation analysis of the AR gene, Scatchard, and SDS-PAGE analysis of the AR protein was performed. Furthermore, steroid 5-alpha-reductase-2 (SRD5A2; 607306) expression and activity in genital skin fibroblasts were investigated, and the SRD5A2 gene was sequenced. The decrease in SHBG serum levels in an SHBG suppression test did not suggest differences in androgen sensitivity as the cause of the phenotypic variation. Also, androgen binding characteristics of the AR, AR expression levels, and the phosphorylation pattern of the AR on hormone binding were identical in both sibs. However, SRD5A2 activity was normal in genital skin fibroblasts from the phenotypic male patient but undetectable in genital skin fibroblasts from the phenotypic female patient. The lack of SRD5A2 activity was due to absent or reduced expression of SRD5A2 in genital skin fibroblasts from the phenotypic female patient. Exon and flanking intron sequences of the SRD5A2 gene showed no mutations in either sib. Therefore, the absent or reduced expression of SRD5A2 is likely to be additional to the AIS. The authors concluded that (1) distinct phenotypic variation in this family was caused by SRD5A2 deficiency, additional to AIS; (2) this 5-alpha-reductase deficiency was due to absence of expression of SRD5A2 as shown by molecular studies, and (3) the distinct phenotypic variation in AIS here is explained by differences in the availability of 5-alpha-dihydrotestosterone during embryonic sex differentiation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, IVS2AS, T-A, -11
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147497386,
|
|
|
|
|
|
|
|
ClinVar: RCV000010518
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bruggenwirth et al. (1997) found an unusual intronic mutation in a family in which 2 brothers and a maternal uncle had partial androgen insensitivity syndrome (312300). All affected individuals were 46,XY and had a female habitus with normal female external genitalia, and normal but underdeveloped testes with epididymides and vasa deferentia present. No mullerian remnants were found. In the coding part and the intron/exon boundaries of the AR gene, no mutation was found. The androgen receptor displayed normal ligand-binding parameters and migrated as a 110- to 112-kD doublet on SDS-PAGE in the absence of hormone. However, after culturing of the patient's genital skin fibroblasts in the presence of hormone, the slower-migrating 114-kD protein, which reflects hormone-dependent phosphorylation, was hardly detectable. Furthermore, receptor protein was undetectable in the nuclear fraction of fibroblasts after treatment with hormone, which is indicative of defective DNA binding. Sequencing of the AR gene revealed a T-to-A transversion 11-bp upstream of exon 3 in intron 2. Analysis of mRNA revealed that splicing involved a cryptic splice site, located 71/70-bp upstream of exon 3, resulting in generation of mRNA with an insert of 69 nucleotides. In addition, a small amount of a transcript with a deleted exon 3 and a very low level of wildtype transcript were detected. Translation of the extended transcript resulted in an androgen receptor protein with 23 amino acid residues inserted between the 2 zinc clusters, displaying defective DNA binding and defective transcription activation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</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>.0042 ANDROGEN INSENSITIVITY, PARTIAL</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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AR, LEU172TER
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<br />
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SNP: rs137852590,
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|
|
ClinVar: RCV000010519
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In an adult patient with a 46,XY karyotype presenting with signs of partial virilization (see 312300) (pubic hair Tanner stage 4 and clitoral enlargement), Holterhus et al. (1997) identified a premature stop codon in exon 1 of the AR gene. A T-to-G transversion in codon 172 of the AR gene was detected that replaced the original TTA (leu) with a premature TGA stop codon. No other family members were affected. Examination of the sequencing gel identified a wildtype allele, indicating a mosaicism. In addition, elimination of the unique AftII recognition site induced by the mutation was incomplete, thus confirming mosaicism. Normal androgen binding studies demonstrated expression of the wildtype AR in the patient's genital skin fibroblasts. Premature stop codons of the AR gene are usually associated with a complete androgen insensitivity syndrome. Holterhus et al. (1997) concluded that somatic mosaicism of the AR gene shifts the phenotype to a higher degree of virilization than expected from the genotype of the mutant allele alone. </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>.0043 ANDROGEN INSENSITIVITY, PARTIAL</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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AR, GLN798GLU
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<br />
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SNP: rs137852591,
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gnomAD: rs137852591,
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ClinVar: RCV000010520, RCV000224621, RCV001519068, RCV002247311, RCV003234899, RCV003982835
|
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|
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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>Wang et al. (1998) screened 234 subjects with defective spermatogenesis and identified an azoospermic subject with a gln798-to-glu (Q798E) substitution of the AR gene product. This germline mutation was not detected in 110 fertile controls, was associated with features of minimal androgen insensitivity in the subject (see 312300), had been related to more severe grades of AR (Bevan et al., 1996), and caused a subtle, but significant, decrease in receptor trans-activation function in vitro that was consistent with the phenotype. Despite being in the middle of the ligand-binding domain of the AR, the Q798E mutation did not cause any ligand-binding defect, indicating that this highly conserved residue has a trans-activation function but does not directly form part of the ligand-binding pocket. The transactivation defect of the mutant receptor can be rectified in vitro with the androgenic drug fluoxymesterone, but not with mesterolone or nortestosterone. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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AR, MET807THR
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<br />
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SNP: rs137852592,
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ClinVar: RCV000010521, RCV003133116
|
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|
|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
<p>Ong et al. (1999) identified a met807-to-thr mutation in the AR gene in a 46,XY infant with partial androgen insensitivity (312300). Treatment with a dihydrotestosterone gel, applied topically to the periscrotal region 3 times a day, for 5 weeks resulted in improved male genital development. The authors stated that in vitro functional assays can help identify the subset of patients with ambiguous genitalia who could respond well to androgen therapy. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 ANDROGEN INSENSITIVITY, COMPLETE</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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|
AR, 1-BP INS, 179A
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<br />
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SNP: rs759327087,
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|
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gnomAD: rs759327087,
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|
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|
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ClinVar: RCV000010522
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|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large kindred with complete androgen insensitivity syndrome (300068), Zhu et al. (1999) identified a mutation in the polymorphic CAG trinucleotide region of exon 1 of the AR gene, where a single A is inserted at nucleotide 179, or equivalently, a GC dinucleotide is deleted at nucleotide 180 (313700.0046). Both mutations result in a frameshift at amino acid 60 and a premature termination of the receptor downstream of the mutation, predicting a mutant AR with only 79 amino acids in the N terminus, which prohibits binding to the ligand as well as the cognate DNA. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0046 ANDROGEN INSENSITIVITY, COMPLETE</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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AR, 2-BP DEL, 180GC
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|
<br />
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|
|
SNP: rs869320731,
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|
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|
|
|
|
ClinVar: RCV000010489
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 313700.0045 and Zhu et al. (1999). </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0047 PROSTATE CANCER SUSCEPTIBILITY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
AR, ARG726LEU
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<br />
|
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|
|
SNP: rs137852593,
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|
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|
|
|
gnomAD: rs137852593,
|
|
|
|
|
|
ClinVar: RCV000010523, RCV002247312, RCV003764545
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Elo et al. (1995) described a germline G-T transversion in exon E of the AR gene, resulting in an arg726-to-leu (R726L) substitution, in a patient with prostate cancer (HPCX3; 301120) from northern Finland. Koivisto et al. (1999) found the same mutation in another Finnish prostate cancer patient when screening for AR mutations by single-strand conformation polymorphism in 6 patients whose cancers appeared during finasteride treatment for benign prostatic hyperplasia. The R726L mutation affected the hormone-binding region in exon E and led to activation of the androgen receptor not only by dihydrotestosterone and testosterone but also by estradiol. The fact that this mutation had not been found in any published studies of the AR gene suggested that it might represent a unique Finnish mutation. Mononen et al. (2000) analyzed the frequency of the R726L mutation in over 1,400 specimens from blood donors, 418 consecutive prostate cancer patients with no family history of prostate cancer, and 106 patients with a positive family history of prostate cancer. Its frequency in blood donors was 3 in 900 (0.33%). In contrast, 8 (1.91%) were mutations found in the prostate cancer group without family history, and 2 (1.89%) were mutations found in the hereditary group. Mononen et al. (2000) suggested that the R726L substitution in the AR gene may confer up to 6-fold increased risk of prostate cancer and may contribute to cancer development in up to 2% of Finnish prostate cancer patients. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0048 ANDROGEN INSENSITIVITY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, SER888SER
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs137852594,
|
|
|
|
|
|
|
|
ClinVar: RCV000010524, RCV001059742, RCV001785450
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with partial androgen sensitivity syndrome (300068), Hellwinkel et al. (2001) identified a single, presumably silent nucleotide variation (AGC to AGT) at codon 888 in exon 8 of the AR gene. However, in the patient's genital skin fibroblasts, a truncated transcript of 5.5 kb (normal: 10.5 kb) was detected, which lacked a part of exon 8 and much of the 3-prime untranslated region. The translation product includes 8 missense amino acids from codon 886 onward followed by a premature stop codon. The mutant protein was shown by in vitro expression analysis to lack any residual function. However, RT-PCR products included 2 additional splicing variants of 6.4 and 7.8 kb in both patient and normal control genital skin fibroblasts. These splicing variants comprise the complete coding region but a shortened 3-prime untranslated region. Thus, a distinct alternative pre-mRNA processing event leading to 2 additional transcripts occurs generally in genital skin fibroblasts. In addition, this process partially prevents aberrant splicing in the patient and produces a small fraction of normal, functional intact AR protein that could explain the partial masculinization in this patient. The authors concluded that an exonic splicing mutation in the AR gene indicates a physiologic relevance of the regular AR mRNA variants with shortened 3-prime untranslated regions and their functional translation products in human genital development. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0049 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, IVS6, G-T, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1602278831,
|
|
|
|
|
|
|
|
ClinVar: RCV000010525
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Sammarco et al. (2000) reported an 11-year-old XY girl, with clinical manifestations of impaired androgen biologic action (312300), including female phenotype, blind-ending vagina, small degree of posterior labial fusion, and absence of uterus, fallopian tubes, and ovaries. At diagnosis the patient had a FSH/LH ratio according to the pubertal stage, undetectable 17-beta-estradiol, and high levels of testosterone (80.1 ng/mL). After bilateral gonadectomy, performed at the age of 11 years, histologic examination showed small embryonic seminiferous tubules containing prevalently Sertoli cells and occasional spermatogonia together with abundant fibrous tissue. Molecular study of the patient showed a G-to-T transversion in position +5 of the donor splice site in the junction between exon 6 and intron 6 of the AR gene. Analysis of RT-PCR products from AR mRNA from cultured genital skin fibroblasts of the patient suggested that splicing was defective, and intron 6 was retained in most of the receptor mRNA molecules. Immunoblotting showed that most of the expressed protein lacked part of the C-terminal hormone-binding domain, and a small amount of normal receptor was observed. The authors concluded that this was probably responsible for the reduced binding capacity in genital skin fibroblasts of the patient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0050 ANDROGEN INSENSITIVITY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, LEU712PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852595,
|
|
|
|
|
|
|
|
ClinVar: RCV000010526
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Holterhus et al. (2000) reported a family with 4 individuals with androgen insensitivity syndrome (300068), 3 brothers (B1-B3) and their uncle, displaying strikingly different external genitalia: B1, ambiguous; B2, severe micropenis; B3, slight micropenis; and uncle, micropenis and penoscrotal hypospadias. All had been assigned a male gender. Holterhus et al. (2000) detected the same leu712-to-phe (CTT-TTT, L712F) AR mutation in each subject. Methyltrienolone binding on cultured genital skin fibroblasts of B2 suggested moderate impairment of the ligand-binding domain. In trans-activation assays, the 712F mutant showed considerable deficiency at low concentrations of testosterone (0.01-0.1 nmol/L) or dihydrotestosterone (0.01 nmol/L). Remarkably, this deficiency could be fully neutralized by testosterone concentrations greater than 1.0 nmol/L. Hence, the 712F AR could switch its function from subnormal to normal within the physiologic concentration range of testosterone. This was reflected by an excellent response to testosterone therapy in B1, B2, and the uncle. The authors concluded that, taking into account the well documented individual and time-dependent variation in testosterone concentration in early fetal development, their observations illustrated the potential impact of varying ligand concentrations for distinct cases of phenotypic variability in AIS. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0051 ANDROGEN INSENSITIVITY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, GLY577ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852596,
|
|
|
|
|
|
|
|
ClinVar: RCV000010527
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Nguyen et al. (2001) characterized a novel mutation of the human androgen receptor (AR), gly577 to arg (G577R), associated with partial androgen insensitivity syndrome (300068). G577 is the first amino acid of the P box, a region crucial for the selectivity of receptor/DNA interaction. Although the equivalent amino acid in the glucocorticoid receptor (GR; 138040), also gly, is not involved in DNA interaction, the residue at the same position in the estrogen receptor (ER; 133430), glu, interacts with the 2 central base pairs in the PuGGTCA motif. The authors observed that the G577R mutation does not induce binding to probes that are not recognized by the wildtype AR. However, binding to the 4 PuGNACA elements recognized by the wildtype AR was affected to different degrees, resulting in an altered selectivity of DNA response element recognition. In particular, the G577R mutant did not interact with PuGGACA palindromes. Modeling of the complex between mutant AR and PuGNACA motifs indicates that the destabilizing effect of the mutation is attributable to a steric clash between the C-beta of arg at position 1 of the P box and the methyl group of the second thymine residue in the TGTTCPy arm of the palindrome. The authors concluded that androgen target genes may be differentially affected by the G577R mutation. They stated that G577R was the first natural mutation characterized that alters the selectivity of the AR/DNA interaction. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
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</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0052 ANDROGEN INSENSITIVITY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, SER865PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852597,
|
|
|
|
|
|
|
|
ClinVar: RCV000010528
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Mongan et al. (2002) reported monozygotic twins diagnosed with complete androgen insensitivity syndrome (AIS; 300068) who each possessed 2 substitutions in the AR gene (C to G at position 2930 and T to C at position 2955, both in exon 7), leading to phe856-to-leu (F856L; 313700.0053) and ser865-to-pro (S865P) mutations, respectively. Neither parent was found to be a carrier for these mutations, indicating that the double mutation arose de novo. Both mutations were recreated by site-directed mutagenesis and compared functionally with the wildtype receptor. The F856L mutation did not affect androgen binding when expressed in COS-1 cells, nor did it decrease androgen-dependent transactivation in transfected HeLa cells. However, the S865P mutation completely ablated androgen binding and transactivation. The authors concluded that replacement of serine by proline at position 865 was sufficient to cause complete AIS in these twins. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0053 ANDROGEN INSENSITIVITY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, PHE856LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852598,
|
|
|
|
|
|
gnomAD: rs137852598,
|
|
|
|
|
|
ClinVar: RCV000010490
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 313700.0052 and Mongan et al. (2002). </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</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>.0054 ANDROGEN INSENSITIVITY SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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AR, ARG840CYS
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<br />
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ClinVar: RCV000010504, RCV000010529, RCV000640474, RCV001269809
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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>Chu et al. (2002) reported an arg840-to-cys (R840C) substitution in the AR gene in a large Chinese pedigree with AIS (300068). The mutant gene may result in infertility for some affected males with or without hypospadias. However, it was also observed that the mutation did not affect the fertility of the other patients. The gonadotropin levels for 1 of these patients were within normal range. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0055 ANDROGEN INSENSITIVITY, COMPLETE</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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AR, HIS689PRO
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<br />
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SNP: rs137852599,
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ClinVar: RCV000010530
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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>Rosa et al. (2002) described a 46,XY phenotypically female patient with all of the characteristics of complete androgen sensitivity (300068), i.e., primary amenorrhea, no axillary or pubic hair, female external genitalia, no uterus, and undescended testes. An A-to-C transition in exon 4 of the AR gene led to a novel missense his689-to-pro (H689P) mutation in the ligand-binding domain of the AR protein. Functional studies demonstrated that the mutated AR is unable to efficiently bind its natural ligand dihydrotestosterone and to trans-activate androgen response elements. The authors concluded that their analysis of the structural consequences of the H689P substitution suggests that this mutation is likely to perturb the conformation of the second helix of the AR ligand-binding domain, which contains residues critical for androgen binding. </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>.0056 ANDROGEN INSENSITIVITY, PARTIAL</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">
|
|
ANDROGEN INSENSITIVITY, COMPLETE, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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AR, GLY743VAL
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<br />
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SNP: rs137852600,
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ClinVar: RCV000010531, RCV000010532, RCV001851781
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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>Nakao et al. (1993) found a gly743-to-val (G743V) substitution in the androgen receptor in a 20-year-old male with partial androgen insensitivity syndrome (312300) manifesting gynecomastia, hypospadias, microphallus, absent pubic hair, and palpable mammary glands. The amino acid substitution arose from a G-to-T transversion in exon 5 of the AR gene. </p><p>Lobaccaro et al. (1993) found this mutation de novo in a French child with complete androgen insensitivity syndrome (300068) and negative receptor binding. They noted that the G743V change is in the hormone binding domain. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0057 ANDROGEN INSENSITIVITY, COMPLETE</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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AR, GLY743GLU
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<br />
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SNP: rs137852600,
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ClinVar: RCV000010533
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with complete androgen insensitivity syndrome (300068), Poujol et al. (2002) found a G-to-A transition in exon 5 of the AR gene that resulted in a gly743-to-glu (G743E) amino acid substitution. The patient was referred for primary amenorrhea, normal breast development, and complete absence of pubic and axillary hair at the age of 15 years. Plasma testosterone levels were within the range for normal males, and the karyotype was 46,XY. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0058 ANDROGEN INSENSITIVITY, COMPLETE</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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AR, INS/DEL, EX5
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<br />
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SNP: rs869320732,
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ClinVar: RCV000010534
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Vilchis et al. (2003) studied a family in which 4 46,XY individuals in 3 sibships of 2 separate generations had complete androgen insensitivity. A novel insertion/deletion mutation in exon 5 of the AR gene was demonstrated. A deletion of 7 bp was replaced by an insertion of 11 nucleotides, which represented a duplication of the adjacent downstream sequence. The mutation resulted in a frameshift that introduced a premature TGA termination signal 9 codons downstream. The rearrangement predicted a truncation of the androgen receptor, thereby deleting a large portion of the ligand-binding domain. They suggested that this represented the first insertion/deletion mutation of the AR gene and that it had arisen by a slipped-strand mispairing mechanism. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0059 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
AR, SER740CYS
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<br />
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|
|
SNP: rs137852601,
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ClinVar: RCV000010535
|
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</span>
|
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</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 61-year-old man with partial androgen insensitivity, Pitteloud et al. (2004) identified a C-to-G transversion in exon 5 of the AR gene, changing serine to cysteine at codon 740 (S740C). Serine-740 is located in the ligand-binding domain of the AR protein. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0060 ANDROGEN INSENSITIVITY, PARTIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
AR, ALA645ASP, SHORT POLYGLYCINE REPEAT, LONG POLYGLUTAMINE REPEAT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800053,
|
|
|
|
|
|
gnomAD: rs1800053,
|
|
|
|
|
|
ClinVar: RCV000010536, RCV000613283, RCV000824699, RCV000995934, RCV002512959, RCV003924823, RCV003982836
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Werner et al. (2006) reported 2 unrelated 46,XY patients with undervirilization and genital malformations. Both patients had a short polyglycine (polyG) repeat of 10 residues and a relatively long polyglutamine (polyQ) repeat of 28 and 30 residues in the transactivation domain of the AR. In addition, both had a rare ala645-to-asp (A645D) substitution. In studies in transfected CHO cells, Werner et al. (2006) found that a short polyG repeat downmodulated AR activity to approximately 60 to 65% of the wildtype receptor. This effect was aggravated by A645D in context of a long polyQ repeat to less than 50% activity. In contrast, in the context of a short polyQ and a short polyG repeat, the A645D mutation rescues AR activity to almost wildtype levels, demonstrating a contradictory effect of this mutation, depending on the size of the polymorphic repeats. Werner et al. (2006) concluded that a combination of a short polyG repeat with a long polyQ repeat and an A645D substitution might explain the observed phenotype of their patients as a form of androgen insensitivity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
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|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Gehring and Tomkins (1974); Grino et al. (1988); Hughes and Evans
|
|
(1986); Jukier et al. (1984); Kaufman et al. (1984); Kaufman et al.
|
|
(1976); Keenan et al. (1974); Lin and Ohno (1981); Lubahn et al.
|
|
(1988); Ohno (1971); Ohno (1977); Pinsky et al. (1984); Pinsky et al.
|
|
(1987); Pinsky et al. (1981); Wilson et al. (1984)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
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|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Abel, A., Walcott, J., Woods, J., Duda, J., Merry, D. E.
|
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<strong>Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice.</strong>
|
|
Hum. Molec. Genet. 10: 107-116, 2001.
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[PubMed: 11152658]
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[Full Text: https://doi.org/10.1093/hmg/10.2.107]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Adachi, H., Kume, A., Li, M., Nakagomi, Y., Niwa, H., Do, J., Sang, C., Kobayashi, Y., Doyu, M., Sobue, G.
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<strong>Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death.</strong>
|
|
Hum. Molec. Genet. 10: 1039-1048, 2001.
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[PubMed: 11331614]
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[Full Text: https://doi.org/10.1093/hmg/10.10.1039]
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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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Aschim, E. L., Nordenskjold, A., Giwercman, A., Lundin, K. B., Ruhayel, Y., Haugen, T. B., Grotmol, T., Giwercman, Y. L.
|
|
<strong>Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene.</strong>
|
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J. Clin. Endocr. Metab. 89: 5105-5109, 2004.
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[PubMed: 15472213]
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[Full Text: https://doi.org/10.1210/jc.2004-0293]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bailey, C. K., Andriola, I. F. M., Kampinga, H. H., Merry, D. E.
|
|
<strong>Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.</strong>
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Hum. Molec. Genet. 11: 515-523, 2002.
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[PubMed: 11875046]
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[Full Text: https://doi.org/10.1093/hmg/11.5.515]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Batch, J. A., Evans, B. A. J., Hughes, I. A., Patterson, M. N.
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<strong>Mutations of the androgen receptor gene identified in perineal hypospadias.</strong>
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J. Med. Genet. 30: 198-201, 1993.
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[PubMed: 8097257]
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[Full Text: https://doi.org/10.1136/jmg.30.3.198]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Batch, J. A., Williams, D. M., Davies, H. R., Brown, B. D., Evans, B. A. J., Hughes, I. A., Patterson, M. N.
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<strong>Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome.</strong>
|
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Hum. Molec. Genet. 1: 497-503, 1992.
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[PubMed: 1307250]
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[Full Text: https://doi.org/10.1093/hmg/1.7.497]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Beitel, L. K., Kazemi-Esfarjani, P., Kaufman, M., Lumbroso, R., DiGeorge, A. M., Killinger, D. W., Trifiro, M. A., Pinsky, L.
|
|
<strong>Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance.</strong>
|
|
J. Clin. Invest. 94: 546-554, 1994.
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|
|
[PubMed: 8040309]
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[Full Text: https://doi.org/10.1172/JCI117368]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Belsham, D. D., Pereira, F., Greenberg, C. R., Liao, S., Wrogemann, K.
|
|
<strong>Leu676-to-pro mutation of the androgen receptor causes complete androgen insensitivity syndrome in a large Hutterite kindred.</strong>
|
|
Hum. Mutat. 5: 28-33, 1995.
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|
[PubMed: 7537149]
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[Full Text: https://doi.org/10.1002/humu.1380050104]
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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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Bevan, C. L., Brown, B. B., Davies, H. R., Evans, B. A. J., Hughes, I. A., Patterson, M. N.
|
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<strong>Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome.</strong>
|
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Hum. Molec. Genet. 5: 265-273, 1996.
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[PubMed: 8824883]
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[Full Text: https://doi.org/10.1093/hmg/5.2.265]
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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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Biancalana, V., Serville, F., Pommier, J., Julien, J., Hanauer, A., Mandel, J. L.
|
|
<strong>Moderate instability of the trinucleotide repeat in spinobulbar muscular atrophy.</strong>
|
|
Hum. Molec. Genet. 1: 255-258, 1992.
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[PubMed: 1303195]
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[Full Text: https://doi.org/10.1093/hmg/1.4.255]
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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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Blessing, A. M., Ganesan, S., Rajapakshe, K., Sung, Y. Y., Bollu, L. R., Shi, Y., Cheung, E., Coarfa, C., Chang, J. T., McDonnell, D. P., Frigo, D. E.
|
|
<strong>Identification of a novel coregulator, SH3YL1, that interacts with the androgen receptor N-terminus.</strong>
|
|
Molec. Endocr. 29: 1426-1439, 2015.
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[PubMed: 26305679]
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[Full Text: https://doi.org/10.1210/me.2015-1079]
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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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Boehmer, A. L. M., Brinkmann, A. O., Bruggenwirth, H., Van Assendelft, C., Otten, B. J., Verleun-Mooijman, M. C. T., Niermeijer, M. F., Brunner, H. G., Rouwe, C. W., Waelkens, J. J., Oostdijk, W., Kleijer, W. J., Van Der Kwast, T. H., De Vroede, M. A., Drop, S. L. S.
|
|
<strong>Genotype versus phenotype in families with androgen insensitivity syndrome.</strong>
|
|
J. Clin. Endocr. Metab. 86: 4151-4160, 2001. Note: Erratum: J. Clin. Endocr. Metab. 87: 3109 only, 2002.
|
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|
|
|
[PubMed: 11549642]
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|
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[Full Text: https://doi.org/10.1210/jcem.86.9.7825]
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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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Boehmer, A. L. M., Brinkmann, A. O., Niermeijer, M. F., Bakker, L., Halley, D. J. J., Drop, S. L. S.
|
|
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Bao Lige - updated : 07/13/2018<br>Patricia A. Hartz - updated : 02/14/2018<br>Paul J. Converse - updated : 01/25/2017<br>Patricia A. Hartz - updated : 11/18/2016<br>Marla J. F. O'Neill - updated : 4/1/2014<br>Ada Hamosh - updated : 10/1/2013<br>Cassandra L. Kniffin - updated : 8/2/2011<br>Ada Hamosh - updated : 6/14/2011<br>George E. Tiller - updated : 2/23/2010<br>George E. Tiller - updated : 10/23/2009<br>John A. Phillips, III - updated : 1/15/2009<br>John A. Phillips, III - updated : 1/13/2009<br>John A. Phillips, III - updated : 6/24/2008<br>Patricia A. Hartz - updated : 4/9/2008<br>John A. Phillips, III - updated : 1/7/2008<br>Marla J. F. O'Neill - updated : 8/22/2007<br>Paul J. Converse - updated : 5/8/2007<br>John A. Phillips, III - updated : 4/9/2007<br>John A. Phillips, III - updated : 4/9/2007<br>George E. Tiller - updated : 1/16/2007<br>Cassandra L. Kniffin - updated : 12/13/2006<br>John A. Phillips, III - updated : 5/23/2006<br>Cassandra L. Kniffin - updated : 4/24/2006<br>John A. Phillips, III - updated : 4/5/2006<br>Marla J. F. O'Neill - updated : 3/23/2006<br>Marla J. F. O'Neill - updated : 3/13/2006<br>Patricia A. Hartz - updated : 11/10/2005<br>Cassandra L. Kniffin - reorganized : 10/28/2005<br>Cassandra L. Kniffin - updated : 10/14/2005<br>Patricia A. Hartz - updated : 9/21/2005<br>John A. Phillips, III - updated : 7/19/2005<br>John A. Phillips, III - updated : 7/13/2005<br>Cassandra L. Kniffin - updated : 6/27/2005<br>Victor A. McKusick - updated : 6/17/2005<br>George E. Tiller - updated : 4/22/2005<br>John A. Phillips, III - updated : 4/1/2005<br>George E. Tiller - updated : 3/21/2005<br>George E. Tiller - updated : 2/17/2005<br>John A. Phillips, III - updated : 8/2/2004<br>John A. Phillips, III - updated : 7/21/2004<br>Victor A. McKusick - updated : 6/15/2004<br>Cassandra L. Kniffin - updated : 11/24/2003<br>George E. Tiller - updated : 9/18/2003<br>Victor A. McKusick - updated : 8/27/2003<br>Victor A. McKusick - updated : 8/5/2003<br>John A. Phillips, III - updated : 7/30/2003<br>George E. Tiller - updated : 7/9/2003<br>John A. Phillips, III - updated : 3/27/2003<br>John A. Phillips, III - updated : 1/8/2003<br>Victor A. McKusick - updated : 1/8/2003<br>George E. Tiller - updated : 11/11/2002<br>George E. Tiller - updated : 10/3/2002<br>Victor A. McKusick - updated : 9/30/2002<br>Stylianos E. Antonarakis - updated : 9/20/2002<br>George E. Tiller - updated : 9/17/2002<br>George E. Tiller - updated : 8/21/2002<br>John A. Phillips, III - updated : 8/8/2002<br>John A. Phillips, III - updated : 8/8/2002<br>John A. Phillips, III - updated : 7/31/2002<br>John A. Phillips, III - updated : 7/25/2002<br>John A. Phillips, III - updated : 7/23/2002<br>Victor A. McKusick - updated : 3/4/2002<br>Victor A. McKusick - updated : 1/24/2002<br>John A. Phillips, III - updated : 11/7/2001<br>Michael B. Petersen - updated : 10/30/2001<br>Victor A. McKusick - updated : 10/15/2001<br>John A. Phillips, III - updated : 10/11/2001<br>John A. Phillips, III - updated : 8/8/2001<br>John A. Phillips, III - updated : 8/3/2001<br>John A. Phillips, III - updated : 7/26/2001<br>Victor A. McKusick - updated : 6/25/2001<br>George E. Tiller - updated : 3/12/2001<br>Carol A. Bocchini - updated : 2/22/2001<br>Victor A. McKusick - updated : 2/7/2001<br>Jane Kelly - updated : 1/18/2001<br>George E. Tiller - updated : 11/17/2000<br>John A. Phillips, III - updated : 8/9/2000<br>George E. Tiller - updated : 5/5/2000<br>John A. Phillips, III - updated : 3/31/2000<br>Wilson H. Y. Lo - updated : 3/21/2000<br>Armand Bottani - updated : 3/14/2000<br>Victor A. McKusick - updated : 2/16/2000<br>Victor A. McKusick - updated : 1/24/2000<br>Victor A. McKusick - updated : 12/22/1999<br>John A. Phillips, III - updated : 11/29/1999<br>Sonja A. Rasmussen - updated : 11/16/1999<br>Wilson H. Y. Lo - updated : 9/2/1999<br>Victor A. McKusick - updated : 4/23/1999<br>Victor A. McKusick - updated : 1/25/1999<br>John A. Phillips, III - updated : 9/29/1998<br>Victor A. McKusick - updated : 3/26/1998<br>John A. Phillips, III - updated : 3/18/1998<br>John A. Phillips, III - updated : 1/3/1998<br>Victor A. McKusick - updated : 11/26/1997<br>John A. Phillips, III - updated : 8/26/1997<br>Victor A. McKusick - updated : 6/12/1997<br>Victor A. McKusick - updated : 5/13/1997<br>Victor A. McKusick - updated : 3/21/1997<br>Victor A. McKusick - updated : 2/28/1997<br>John A. Phillips, III - updated : 12/20/1996<br>Cynthia K. Ewing - updated : 10/14/1996<br>John A. Phillips, III - updated : 9/21/1996
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Victor A. McKusick : 6/4/1986
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Edit History:
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carol : 07/12/2024<br>carol : 11/08/2023<br>carol : 11/07/2023<br>carol : 09/25/2022<br>carol : 02/14/2022<br>carol : 11/01/2019<br>carol : 06/13/2019<br>carol : 02/12/2019<br>carol : 09/11/2018<br>mgross : 07/13/2018<br>mgross : 02/14/2018<br>alopez : 02/02/2017<br>mgross : 01/25/2017<br>mgross : 11/18/2016<br>carol : 09/09/2016<br>carol : 04/02/2014<br>mcolton : 4/1/2014<br>alopez : 10/1/2013<br>terry : 4/1/2013<br>terry : 1/2/2013<br>alopez : 12/11/2012<br>terry : 11/28/2012<br>terry : 9/25/2012<br>terry : 6/7/2012<br>terry : 5/17/2012<br>carol : 2/27/2012<br>terry : 10/10/2011<br>alopez : 10/6/2011<br>joanna : 10/3/2011<br>wwang : 8/9/2011<br>ckniffin : 8/2/2011<br>ckniffin : 8/2/2011<br>ckniffin : 8/2/2011<br>alopez : 6/16/2011<br>terry : 6/14/2011<br>carol : 5/23/2011<br>carol : 5/11/2011<br>terry : 11/3/2010<br>terry : 9/9/2010<br>wwang : 2/25/2010<br>terry : 2/23/2010<br>wwang : 11/2/2009<br>terry : 10/23/2009<br>carol : 9/15/2009<br>wwang : 6/5/2009<br>ckniffin : 5/28/2009<br>carol : 2/20/2009<br>ckniffin : 2/20/2009<br>carol : 1/23/2009<br>alopez : 1/15/2009<br>alopez : 1/13/2009<br>alopez : 12/29/2008<br>mgross : 11/17/2008<br>wwang : 10/14/2008<br>terry : 9/26/2008<br>alopez : 6/26/2008<br>alopez : 6/24/2008<br>alopez : 5/2/2008<br>alopez : 5/1/2008<br>mgross : 4/11/2008<br>terry : 4/9/2008<br>carol : 1/7/2008<br>carol : 9/4/2007<br>wwang : 8/29/2007<br>terry : 8/22/2007<br>mgross : 5/14/2007<br>terry : 5/8/2007<br>carol : 4/9/2007<br>carol : 4/9/2007<br>wwang : 1/23/2007<br>terry : 1/16/2007<br>carol : 1/10/2007<br>wwang : 12/18/2006<br>ckniffin : 12/13/2006<br>carol : 11/27/2006<br>alopez : 8/23/2006<br>alopez : 5/23/2006<br>wwang : 5/9/2006<br>ckniffin : 4/24/2006<br>alopez : 4/5/2006<br>wwang : 3/23/2006<br>wwang : 3/23/2006<br>wwang : 3/17/2006<br>terry : 3/13/2006<br>mgross : 11/29/2005<br>mgross : 11/29/2005<br>terry : 11/10/2005<br>carol : 10/28/2005<br>ckniffin : 10/14/2005<br>wwang : 9/26/2005<br>wwang : 9/21/2005<br>alopez : 7/19/2005<br>alopez : 7/13/2005<br>carol : 7/5/2005<br>wwang : 7/1/2005<br>ckniffin : 6/27/2005<br>alopez : 6/21/2005<br>terry : 6/17/2005<br>tkritzer : 4/22/2005<br>alopez : 4/1/2005<br>alopez : 3/21/2005<br>terry : 3/16/2005<br>wwang : 2/22/2005<br>terry : 2/17/2005<br>terry : 2/17/2005<br>carol : 12/14/2004<br>alopez : 8/2/2004<br>ckniffin : 7/26/2004<br>alopez : 7/21/2004<br>tkritzer : 6/22/2004<br>terry : 6/15/2004<br>carol : 4/27/2004<br>tkritzer : 4/8/2004<br>carol : 12/8/2003<br>ckniffin : 11/24/2003<br>cwells : 11/5/2003<br>cwells : 9/18/2003<br>cwells : 8/29/2003<br>terry : 8/27/2003<br>tkritzer : 8/11/2003<br>tkritzer : 8/5/2003<br>tkritzer : 8/5/2003<br>alopez : 7/30/2003<br>terry : 7/28/2003<br>cwells : 7/9/2003<br>alopez : 3/27/2003<br>alopez : 1/8/2003<br>cwells : 1/8/2003<br>terry : 11/15/2002<br>alopez : 11/11/2002<br>alopez : 10/21/2002<br>carol : 10/18/2002<br>mgross : 10/18/2002<br>cwells : 10/3/2002<br>mgross : 10/1/2002<br>carol : 9/30/2002<br>mgross : 9/20/2002<br>cwells : 9/17/2002<br>cwells : 8/21/2002<br>cwells : 8/8/2002<br>cwells : 8/8/2002<br>tkritzer : 7/31/2002<br>tkritzer : 7/31/2002<br>tkritzer : 7/25/2002<br>tkritzer : 7/25/2002<br>tkritzer : 7/23/2002<br>carol : 3/14/2002<br>mgross : 3/11/2002<br>terry : 3/4/2002<br>carol : 2/21/2002<br>carol : 2/6/2002<br>mcapotos : 2/4/2002<br>terry : 1/24/2002<br>cwells : 11/9/2001<br>alopez : 11/8/2001<br>alopez : 11/7/2001<br>cwells : 10/30/2001<br>carol : 10/29/2001<br>mcapotos : 10/15/2001<br>alopez : 10/11/2001<br>alopez : 8/8/2001<br>alopez : 8/3/2001<br>alopez : 7/26/2001<br>mcapotos : 7/6/2001<br>mcapotos : 6/29/2001<br>terry : 6/25/2001<br>cwells : 3/27/2001<br>terry : 3/21/2001<br>cwells : 3/12/2001<br>cwells : 3/7/2001<br>mcapotos : 2/22/2001<br>mcapotos : 2/22/2001<br>carol : 2/22/2001<br>carol : 2/20/2001<br>mcapotos : 2/12/2001<br>mcapotos : 2/9/2001<br>terry : 2/7/2001<br>cwells : 1/23/2001<br>terry : 1/18/2001<br>mcapotos : 11/29/2000<br>terry : 11/17/2000<br>mgross : 8/9/2000<br>alopez : 5/5/2000<br>mgross : 4/28/2000<br>terry : 3/31/2000<br>carol : 3/21/2000<br>carol : 3/14/2000<br>mgross : 3/9/2000<br>terry : 2/16/2000<br>carol : 1/30/2000<br>terry : 1/24/2000<br>mcapotos : 1/7/2000<br>mcapotos : 1/4/2000<br>terry : 12/22/1999<br>alopez : 11/29/1999<br>alopez : 11/29/1999<br>mgross : 11/16/1999<br>mgross : 11/16/1999<br>carol : 9/2/1999<br>mgross : 5/12/1999<br>mgross : 4/29/1999<br>terry : 4/23/1999<br>mgross : 2/5/1999<br>terry : 1/25/1999<br>carol : 9/29/1998<br>alopez : 3/26/1998<br>terry : 3/20/1998<br>psherman : 3/18/1998<br>psherman : 3/18/1998<br>alopez : 1/27/1998<br>alopez : 1/27/1998<br>alopez : 1/26/1998<br>jenny : 12/2/1997<br>terry : 11/26/1997<br>jenny : 10/22/1997<br>alopez : 6/26/1997<br>carol : 6/23/1997<br>mark : 6/18/1997<br>terry : 6/12/1997<br>jenny : 5/21/1997<br>jenny : 5/21/1997<br>mark : 5/14/1997<br>mark : 5/14/1997<br>jenny : 5/13/1997<br>terry : 5/7/1997<br>terry : 3/21/1997<br>terry : 3/17/1997<br>mark : 2/28/1997<br>terry : 2/26/1997<br>jamie : 11/20/1996<br>jamie : 11/20/1996<br>mark : 11/19/1996<br>mark : 11/16/1996<br>mark : 11/16/1996<br>mark : 11/16/1996<br>mark : 11/8/1996<br>mark : 11/8/1996<br>mark : 11/8/1996<br>terry : 10/24/1996<br>jamie : 10/23/1996<br>jamie : 10/16/1996<br>jamie : 10/14/1996<br>mark : 9/29/1996<br>terry : 9/23/1996<br>carol : 9/21/1996<br>mark : 8/29/1996<br>mark : 3/30/1996<br>terry : 3/26/1996<br>terry : 3/12/1996<br>mark : 1/21/1996<br>terry : 1/18/1996<br>pfoster : 11/15/1995<br>mark : 10/2/1995<br>terry : 3/3/1995<br>davew : 7/28/1994<br>mimadm : 6/26/1994<br>warfield : 4/20/1994
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