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Entry
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- *480000 - SEX-DETERMINING REGION Y; SRY
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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">*480000</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotype">Genotype</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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</li>
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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/480000">Table View</a>
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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 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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</ul>
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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=ENSG00000184895;t=ENST00000383070" 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=6736" 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=480000" 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=ENSG00000184895;t=ENST00000383070" 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_003140" 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_003140" 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=480000" 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=08364&isoform_id=08364_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/SRY" 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/36605,263859,292512,292514,298528,347962,548983,1216158,4507225,17384045,32815783,32815787,32815789,32815791,45934750,47681281,47681283,47834752,47834754,47834756,47834758,47834760,47834762,47834764,47834766,47834768,49901836,49902356,55774955,55775710,62719824,62719826,62719828,62822611,62822612,62822613,62822614,62822615,68235748,68235750,157310116,157310118,157310120,157310122,157310124,157310126,262289731,262289733,262289735,262289737,268322327,268322329,268322331,268322333,268322335,268322337,268322339,268322341,268322343,268322345,268322347,268322349,268322351,268322353,268322355,268322357,268322359,268322361,268322363,268322365,268322367,268322369,295656580,295656582,299013815,299013817,299013819,299013821,299013823,299013825,299013827,299013829,299013831,299013833,299013835,299013837,299737437,299737439,299737441,299737443,299737445,299737447,340366101,340366103,340366106,340366108,340366110,383087935,383087937,383087939,383087941,383087943,383087945,383087947,383087949,383087952,383087955,383087957,383087959,383087961,383087963,383087965,383087968,383087970,383087972,383087974,383087976,383087978,383087980,383087982,383087984,383087987,383087989,383087991,556559952,556559954,556559956,556559958,556559961,556559963,556559965,556559970,1208991285,1567442222,1567442224,1567442226,1567442228,1567442230,1567442232,1567442234,1567442236,1567442238,1567442240,1567442242,1567442244,1567442246,1567442248,1567442250" 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/Q05066" 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=6736" 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=ENSG00000184895;t=ENST00000383070" 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=SRY" 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=SRY" 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+6736" 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/SRY" 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:6736" 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/6736" 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=chrY&hgg_gene=ENST00000383070.2&hgg_start=2786855&hgg_end=2787682&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">
|
|
<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:11311" 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://medlineplus.gov/genetics/gene/sry" 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=480000[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=480000[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000184895" 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.gwascentral.org/search?q=SRY" 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=SRY" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SRY&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/PA36135" 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:11311" 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:98660" 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/SRY#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:98660" 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/6736/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/results?search_type=advanced&omia_id=001230,002047" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6736" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00015716;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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</div>
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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">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<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>
|
|
</div>
|
|
</a>
|
|
</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://reactome.org/content/query?q=SRY&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>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<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> 763683004<br />
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">ICD+</a>
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</div>
|
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<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
480000
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
|
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|
|
SEX-DETERMINING REGION Y; SRY
|
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|
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</span>
|
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</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
TESTIS-DETERMINING FACTOR; TDF<br />
|
|
TESTIS-DETERMINING FACTOR ON Y; TDY
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</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=SRY" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SRY</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/Y/13?start=-3&limit=10&highlight=13">Yp11.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrY:2786855-2787682&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'})">Y:2,786,855-2,787,682</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=400045,400044" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/Y/13?start=-3&limit=10&highlight=13">
|
|
Yp11.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
46XX sex reversal 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/400045"> 400045 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved">4</abbr>
|
|
|
|
</span>
|
|
</td>
|
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|
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|
|
</tr>
|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
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PheneGene Graphics <span class="caret"></span>
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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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<p>SRY encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA binding proteins.</p>
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<p><a href="#67" class="mim-tip-reference" title="Sinclair, A. H., Berta, P., Palmer, M. S., Hawkins, R., Griffiths, B. L., Smith, M., Foster, J. W., Frischauf, A.-M., Lovell-Badge, R., Goodfellow, P. N. <strong>A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif..</strong> Nature 346: 240-245, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695712</a>] [<a href="https://doi.org/10.1038/346240a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695712">Sinclair et al. (1990)</a> identified a gene, which they named SRY (sex-determining region Y), within a 35-kb sex-determining region on the human Y chromosome that was adjacent to the pseudoautosomal boundary. The mouse homolog Sry was subsequently cloned and found to be present in Sxr-prime mice, which have the smallest part of the Y chromosome known to be sex-determining (<a href="#27" class="mim-tip-reference" title="Gubbay, J., Collignon, J., Koopman, P., Capel, B., Economou, A., Munsterberg, A., Vivian, N., Goodfellow, P. N., Lovell-Badge, R. <strong>A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes.</strong> Nature 346: 245-250, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2374589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2374589</a>] [<a href="https://doi.org/10.1038/346245a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2374589">Gubbay et al., 1990</a>). Furthermore, Sry was deleted from a mutant Y chromosome that was no longer sex-determining (<a href="#27" class="mim-tip-reference" title="Gubbay, J., Collignon, J., Koopman, P., Capel, B., Economou, A., Munsterberg, A., Vivian, N., Goodfellow, P. N., Lovell-Badge, R. <strong>A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes.</strong> Nature 346: 245-250, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2374589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2374589</a>] [<a href="https://doi.org/10.1038/346245a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2374589">Gubbay et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2374589+1695712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#68" class="mim-tip-reference" title="Su, H., Lau, Y.-F. C. <strong>Identification of the transcriptional unit, structural organization, and promoter sequence of the human sex-determining region Y (SRY) gene, using a reverse genetic approach.</strong> Am. J. Hum. Genet. 52: 24-38, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8434602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8434602</a>]" pmid="8434602">Su and Lau (1993)</a> found that the SRY open reading frame encodes a deduced 204-amino acid protein with a calculated molecular mass of 24 kD. There is a DNA-binding HMG motif in the middle of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8434602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Capel, B., Swain, A., Nicolis, S., Hacker, A., Walter, M., Koopman, P., Goodfellow, P., Lovell-Badge, R. <strong>Circular transcripts of the testis-determining gene Sry in adult mouse testis.</strong> Cell 73: 1019-1030, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7684656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7684656</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90279-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7684656">Capel et al. (1993)</a> found that a circular Sry transcript consisting of a single exon represented more than 90% of Sry transcripts in adult mouse testis. In contrast, developing mouse genital ridge exclusively expressed linear Sry transcripts. Circular Sry transcripts were not detected in any other mouse tissue examined and were most likely noncoding. <a href="#11" class="mim-tip-reference" title="Capel, B., Swain, A., Nicolis, S., Hacker, A., Walter, M., Koopman, P., Goodfellow, P., Lovell-Badge, R. <strong>Circular transcripts of the testis-determining gene Sry in adult mouse testis.</strong> Cell 73: 1019-1030, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7684656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7684656</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90279-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7684656">Capel et al. (1993)</a> noted that the human SRY gene is transcribed into a linear form only and lacks the flanking inverted repeats required for circular splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7684656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#26" class="mim-tip-reference" title="Goodfellow, P. N., Lovell-Badge, R. <strong>SRY and sex determination in mammals.</strong> Annu. Rev. Genet. 27: 71-92, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8122913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8122913</a>] [<a href="https://doi.org/10.1146/annurev.ge.27.120193.000443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8122913">Goodfellow and Lovell-Badge (1993)</a> provided a major review of SRY and sex determination in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8122913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the study of normal males and females, persons with abnormal numbers of sex chromosomes, and persons carrying variant Y chromosomes, a factor (or factors) that determines the differentiation of the indifferent gonads into testes is known to be located on the Y chromosome and specifically on the short arm; this was designated testis-determining factor (TDF) in the 1960s. (See Mendelian Inheritance in Man, 4th ed., figure 1, page lix, 1975.)</p><p><a href="#54" class="mim-tip-reference" title="Mittwoch, U. <strong>Sex determination and sex reversal: genotype, phenotype, dogma and semantics.</strong> Hum. Genet. 89: 467-479, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634224</a>] [<a href="https://doi.org/10.1007/BF00219168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1634224">Mittwoch (1992)</a> argued that the 'dogma' that all differences distinguishing male and female mammals can be traced to the presence or absence of a single gene encoding a testis-determining factor lacks, as she said, 'biological validity.' She suggested that the genotype of the functional, i.e., fertile, male differs from that of a functional female by the presence of multiple Y-chromosomal genes in association with but a single X chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1634224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#47" class="mim-tip-reference" title="Lahr, G., Maxson, S. C., Mayer, A., Just, W., Pilgrim, C., Reisert, I. <strong>Transcription of the Y chromosomal gene, Sry, in adult mouse brain.</strong> Molec. Brain Res. 33: 179-182, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774960</a>] [<a href="https://doi.org/10.1016/0169-328x(95)00136-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8774960">Lahr et al. (1995)</a> used RT-PCR to investigate the transcription of the Sry gene in mice. The gene was transcribed in the hypothalamus, midbrain, and testis of adult male but not adult female mice. Whereas the transcripts in the adult testis were circular, those in brain were linear and therefore capable of translation. <a href="#47" class="mim-tip-reference" title="Lahr, G., Maxson, S. C., Mayer, A., Just, W., Pilgrim, C., Reisert, I. <strong>Transcription of the Y chromosomal gene, Sry, in adult mouse brain.</strong> Molec. Brain Res. 33: 179-182, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774960</a>] [<a href="https://doi.org/10.1016/0169-328x(95)00136-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8774960">Lahr et al. (1995)</a> hypothesized that some male specific properties of the brain may be generated directly by the SRY gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8774960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>With use of reporter plasmids, gel shift assays, and transfection experiments, <a href="#35" class="mim-tip-reference" title="Hossain, A., Saunders, G. F. <strong>The human sex-determining gene SRY is a direct target of WT1.</strong> J. Biol. Chem. 276: 16817-16823, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278460</a>] [<a href="https://doi.org/10.1074/jbc.M009056200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278460">Hossain and Saunders (2001)</a> determined that the product of the WT1 gene (<a href="/entry/607102">607102</a>) transactivates SRY by binding to its promoter region. They also found that WT1 carrying any of 4 common mutations causing Denys-Drash syndrome failed to activate the SRY promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11278460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#49" class="mim-tip-reference" title="Li, B., Zhang, W., Chan, G., Jancso-Radek, A., Liu, S., Weiss, M. A. <strong>Human sex reversal due to impaired nuclear localization of SRY: a clinical correlation.</strong> J. Biol. Chem. 276: 46480-46484, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11641389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11641389</a>] [<a href="https://doi.org/10.1074/jbc.C100388200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11641389">Li et al. (2001)</a> found that the R133W SRY mutation (<a href="/entry/607102#0019">607102.0019</a>), which lies within the HMG DNA-binding domain, had little or no effect on specific DNA binding and bending assays, but resulted in a significant change in cellular location of SRY upon transfection into COS-7 cells and into a male rat gonadal ridge embryogenic cell line. In both model cell systems, wildtype SRY localized to the nuclear compartment, whereas the mutant SRY showed a broad distribution in the cytoplasm and nucleus similar to that observed with deletion of the C-terminal nuclear localization signal (NLS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11641389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#64" class="mim-tip-reference" title="Sekido, R., Lovell-Badge, R. <strong>Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.</strong> Nature 453: 930-934, 2008. Note: Erratum: Nature 456: 824 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454134</a>] [<a href="https://doi.org/10.1038/nature06944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454134">Sekido and Lovell-Badge (2008)</a> demonstrated that Sry binds to multiple elements within a Sox9 (<a href="/entry/608160">608160</a>) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with steroidogenic factor-1 (SF1) an orphan nuclear receptor encoded by the gene Nr5a1 (<a href="/entry/184757">184757</a>). Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. <a href="#64" class="mim-tip-reference" title="Sekido, R., Lovell-Badge, R. <strong>Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.</strong> Nature 453: 930-934, 2008. Note: Erratum: Nature 456: 824 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454134</a>] [<a href="https://doi.org/10.1038/nature06944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454134">Sekido and Lovell-Badge (2008)</a> concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18454134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 yeast 2-hybrid screening of a human testis cDNA library, <a href="#61" class="mim-tip-reference" title="Sato, Y., Yano, S., Ewis, A. A., Nakahori, Y. <strong>SRY interacts with ribosomal proteins S7 and L13a in nuclear speckles.</strong> Cell Biol. Int. 35: 449-452, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21114473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21114473</a>] [<a href="https://doi.org/10.1042/CBI20090201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21114473">Sato et al. (2011)</a> identified RPS7 (<a href="/entry/603658">603658</a>) and RPL13A (<a href="/entry/619225">619225</a>) as SRY-interacting proteins. Pull-down assay confirmed that the HMG box of SRY was required for its interaction with RPS7 and RPL13A. In transiently transfected COS1 cells, SRY, RPS7, and RPL13A colocalized in nuclear speckles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21114473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K. <strong>Natural RNA circles function as efficient microRNA sponges.</strong> Nature 495: 384-388, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23446346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23446346</a>] [<a href="https://doi.org/10.1038/nature11993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23446346">Hansen et al. (2013)</a> found that the mouse Sry circular RNA contains 16 putative microRNA-138 (MIR138; see <a href="/entry/613394">613394</a>)-binding sites. They showed that Sry bound Mir138 and functioned as an Mir138 sponge, reducing the ability of Mir138 to downregulate expression of a reporter gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23446346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Kuroki, S., Matoba, S., Akiyoshi, M., Matsumura, Y., Miyachi, H., Mise, N., Abe, K., Ogura, A., Wilhelm, D., Koopman, P., Nozaki, M., Kanai, Y., Shinkai, Y., Tachibana, M. <strong>Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a.</strong> Science 341: 1106-1109, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24009392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24009392</a>] [<a href="https://doi.org/10.1126/science.1239864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24009392">Kuroki et al. (2013)</a> found that Jmjd1a (<a href="/entry/611512">611512</a>) regulates expression of the mammalian Y chromosome Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks. <a href="#46" class="mim-tip-reference" title="Kuroki, S., Matoba, S., Akiyoshi, M., Matsumura, Y., Miyachi, H., Mise, N., Abe, K., Ogura, A., Wilhelm, D., Koopman, P., Nozaki, M., Kanai, Y., Shinkai, Y., Tachibana, M. <strong>Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a.</strong> Science 341: 1106-1109, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24009392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24009392</a>] [<a href="https://doi.org/10.1126/science.1239864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24009392">Kuroki et al. (2013)</a> found that Jmjd1a-null mice that were XY were frequently sex reversed, either partially, with a testis and an ovary (12 of 58 animals), or completely, with 2 ovaries (34 of 58 animals). In contrast, all Jmjd1a wildtype and heterozygous XY mice had 2 testes. <a href="#46" class="mim-tip-reference" title="Kuroki, S., Matoba, S., Akiyoshi, M., Matsumura, Y., Miyachi, H., Mise, N., Abe, K., Ogura, A., Wilhelm, D., Koopman, P., Nozaki, M., Kanai, Y., Shinkai, Y., Tachibana, M. <strong>Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a.</strong> Science 341: 1106-1109, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24009392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24009392</a>] [<a href="https://doi.org/10.1126/science.1239864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24009392">Kuroki et al. (2013)</a> concluded that their studies revealed a pivotal role of histone demethylation in mammalian sex determination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24009392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#68" class="mim-tip-reference" title="Su, H., Lau, Y.-F. C. <strong>Identification of the transcriptional unit, structural organization, and promoter sequence of the human sex-determining region Y (SRY) gene, using a reverse genetic approach.</strong> Am. J. Hum. Genet. 52: 24-38, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8434602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8434602</a>]" pmid="8434602">Su and Lau (1993)</a> determined that SRY is an intronless gene that spans 3.8 kb. Analysis of the proximal flanking region revealed 2 GC-rich regions containing several Sp1 (<a href="/entry/189906">189906</a>)-binding sites. The gene also contains a TATAAA motif for the binding of TFIID (TAF5; <a href="/entry/601787">601787</a>) and a kappa B enhancer element for the binding of NF-kappa-B (see <a href="/entry/164011">164011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8434602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>TDF was ultimately mapped to the human Y chromosome by molecular examination of sex-reversed patients. Analysis of 4 XX males with testes who had minute portions of the Y material translocated to the X chromosome was critical in defining the sex-determining region on the human Y chromosome (<a href="#59" class="mim-tip-reference" title="Palmer, M. S., Sinclair, A. H., Berta, P., Ellis, N. A., Goodfellow, P. N., Abbas, N. E., Fellous, M. <strong>Genetic evidence that ZFY is not the testis-determining factor.</strong> Nature 342: 937-939, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594087</a>] [<a href="https://doi.org/10.1038/342937a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594087">Palmer et al., 1989</a>; <a href="#67" class="mim-tip-reference" title="Sinclair, A. H., Berta, P., Palmer, M. S., Hawkins, R., Griffiths, B. L., Smith, M., Foster, J. W., Frischauf, A.-M., Lovell-Badge, R., Goodfellow, P. N. <strong>A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif..</strong> Nature 346: 240-245, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695712</a>] [<a href="https://doi.org/10.1038/346240a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695712">Sinclair et al., 1990</a>). The sex-determining region on the human Y chromosome was later defined to a 35-kb region of Y-specific DNA adjacent to the pseudoautosomal boundary (<a href="#67" class="mim-tip-reference" title="Sinclair, A. H., Berta, P., Palmer, M. S., Hawkins, R., Griffiths, B. L., Smith, M., Foster, J. W., Frischauf, A.-M., Lovell-Badge, R., Goodfellow, P. N. <strong>A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif..</strong> Nature 346: 240-245, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695712</a>] [<a href="https://doi.org/10.1038/346240a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695712">Sinclair et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2594087+1695712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Behlke, M. A., Bogan, J. S., Beer-Romero, P., Page, D. C. <strong>Evidence that the SRY protein is encoded by a single exon on the human Y chromosome.</strong> Genomics 17: 736-739, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8244390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8244390</a>] [<a href="https://doi.org/10.1006/geno.1993.1395" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8244390">Behlke et al. (1993)</a> found that 2 RNAs hybridized to a 4,741-bp genomic segment of the sex-determining region of the human Y chromosome: one transcript deriving from SRY, and a second transcript cross-hybridizing to a pseudogene located 2.5 kb 5-prime of the SRY open reading frame. Analysis of the SRY transcript suggested that the entire SRY protein is encoded by a single exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8244390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>46,XY Complete Gonadal Dysgenesis</em></strong></p><p>
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<a href="#38" class="mim-tip-reference" title="Jager, R. J., Anvret, M., Hall, K., Scherer, G. <strong>A human XY female with a frame shift mutation in the candidate testis-determining gene SRY.</strong> Nature 348: 452-454, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2247151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2247151</a>] [<a href="https://doi.org/10.1038/348452a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2247151">Jager et al. (1990)</a> analyzed the SRY gene in 12 XY sex-reversed females (<a href="/entry/400044">400044</a>) and identified a de novo 4-bp deletion (<a href="#0001">480000.0001</a>) in a conserved DNA-binding motif in 1 patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2247151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Goodfellow, P. N., Migeon, C. J., Smith, K. D., Berkovitz, G. D. <strong>Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis.</strong> Am. J. Hum. Genet. 51: 979-984, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415266</a>]" pmid="1415266">Hawkins et al. (1992)</a> studied the SRY gene in 5 phenotypic females with complete gonadal dysgenesis and a 46,XY karyotype reported by <a href="#4" class="mim-tip-reference" title="Berkovitz, G. D., Fechner, P. Y., Zacur, H. W., Rock, J. A., Snyder, H. M., III, Migeon, C. J., Perlman, E. J. <strong>Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation.</strong> Medicine 70: 375-383, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1956279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1956279</a>] [<a href="https://doi.org/10.1097/00005792-199111000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1956279">Berkovitz et al. (1991)</a>. They used single-strand conformation polymorphism assay and DNA sequencing to screen the open reading frame and identified mutations in 3 of the 5 patients. Like all the previously described SRY mutations, these mutations--2 point mutations (<a href="#0006">480000.0006</a> and <a href="#0007">480000.0007</a>) and a single-base deletion (<a href="#0008">480000.0008</a>)--altered the putative DNA-binding region of the SRY protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1415266+1956279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Hawkins, J. R. <strong>Mutational analysis of SRY in XY females.</strong> Hum. Mutat. 2: 347-350, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8257986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8257986</a>] [<a href="https://doi.org/10.1002/humu.1380020504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8257986">Hawkins (1993)</a> performed a mutation analysis of the SRY gene in XY females. He noted that 11 mutations had been described at that time, and all were within the DNA-binding HMG-box region of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8257986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Cameron, F. J., Sinclair, A. H. <strong>Mutations in SRY and SOX9: testis-determining genes.</strong> Hum. Mutat. 9: 388-395, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143916</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<388::AID-HUMU2>3.0.CO;2-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143916">Cameron and Sinclair (1997)</a> stated that 26 different mutations in the SRY gene have been found in individuals with a 46,XY karyotype. They cited reports stating that no polymorphisms had been described in SRY among 50 normal males. De novo mutations in the SRY HMG-box region almost always resulted in 46,XY unambiguous females with no testicular differentiation. They found 5 reports of familial 46,XY complete gonadal dysgenesis associated with mutations in the SRY HMG-box region. In 4 of these reports, the father carried the same SRY mutation as his 46,XY daughter. None of the mutations appeared to be polymorphisms. Explanations for the sex reversal associated with these familial SRY mutations included paternal gonadal mosaicism for the mutation (yet to be proven) and incomplete penetrance of the mutation. Support for a penetrance effect came from murine studies in which at least 3 autosomal recessive alleles were found to interact with Y-chromosome alleles, resulting in the genesis of XY ovaries and true hermaphrodites (<a href="#19" class="mim-tip-reference" title="Eicher, E. M., Washburn, L. L. <strong>Genetic control of primary sex determination in mice.</strong> Annu. Rev. Genet. 20: 327-360, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3545061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3545061</a>] [<a href="https://doi.org/10.1146/annurev.ge.20.120186.001551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3545061">Eicher and Washburn, 1986</a>). <a href="#9" class="mim-tip-reference" title="Cameron, F. J., Sinclair, A. H. <strong>Mutations in SRY and SOX9: testis-determining genes.</strong> Hum. Mutat. 9: 388-395, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143916</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<388::AID-HUMU2>3.0.CO;2-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143916">Cameron and Sinclair (1997)</a> noted that timing and expression of SRY are exquisitely regulated and probably must reach a threshold. Consequently, a given mutation in SRY against a particular genetic background might produce sufficient SRY expression to reach the threshold required; testis formation can then ensue, accounting for an unaffected father. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9143916+3545061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#72" class="mim-tip-reference" title="Uehara, S., Hashiyada, M., Sato, K., Nata, M., Funato, T., Okamura, K. <strong>Complete XY gonadal dysgenesis and aspects of the SRY genotype and gonadal tumor formation.</strong> J. Hum. Genet. 47: 279-284, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111377</a>] [<a href="https://doi.org/10.1007/s100380200040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111377">Uehara et al. (2002)</a> found missense mutations in the SRY gene in 2 of 3 patients with the complete form of XY gonadal dysgenesis. Combined with the results of a previous study (<a href="#71" class="mim-tip-reference" title="Uehara, S., Funato, T., Yaegashi, N., Suzuki, H., Sato, J., Sasaki, T., Yajima, A. <strong>SRY mutation and tumor formation on the gonads of XY pure gonadal dysgenesis patients.</strong> Cancer Genet. Cytogenet. 113: 78-84, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10459352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10459352</a>] [<a href="https://doi.org/10.1016/s0165-4608(99)00010-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10459352">Uehara et al., 1999</a>) in which 2 of 3 complete-type patients showed SRY abnormalities, the incidence was estimated at 67%, which is higher than previously thought. A metaanalysis of patients with SRY abnormalities showed an incidence of 52.5% for gonadal tumor formation in patients with SRY abnormalities. <a href="#72" class="mim-tip-reference" title="Uehara, S., Hashiyada, M., Sato, K., Nata, M., Funato, T., Okamura, K. <strong>Complete XY gonadal dysgenesis and aspects of the SRY genotype and gonadal tumor formation.</strong> J. Hum. Genet. 47: 279-284, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111377</a>] [<a href="https://doi.org/10.1007/s100380200040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111377">Uehara et al. (2002)</a> gave a useful tabulation of the SRY abnormalities that had been described. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10459352+12111377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Harley, V. R., Layfield, S., Mitchell, C. L., Forwood, J. K., John, A. P., Briggs, L. J., McDowall, S. G., Jans, D. A. <strong>Defective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations.</strong> Proc. Nat. Acad. Sci. 100: 7045-7050, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12764225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12764225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12764225[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.1137864100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12764225">Harley et al. (2003)</a> examined the SRY gene from 4 XY females, each with a missense mutation of a conserved arginine in either 1 of the 2 NLSs of the SRY HMG box. In all cases, mutant SRY protein was partly localized to the cytoplasm, whereas wildtype SRY was strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins and requires cytoplasmic transport factors, whereas the C-terminal NLS is recognized by importin-beta (KPNB1; <a href="/entry/602738">602738</a>). The SRY mutant R133W (<a href="#0019">480000.0019</a>) showed reduced importin-beta binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the 3 other N-terminal NLS mutants examined, 1 unexpectedly showed a marked reduction in importin-beta binding, whereas the other 2 showed normal importin-beta binding, suggesting defects in the importin-independent pathway. <a href="#31" class="mim-tip-reference" title="Harley, V. R., Layfield, S., Mitchell, C. L., Forwood, J. K., John, A. P., Briggs, L. J., McDowall, S. G., Jans, D. A. <strong>Defective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations.</strong> Proc. Nat. Acad. Sci. 100: 7045-7050, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12764225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12764225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12764225[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.1137864100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12764225">Harley et al. (2003)</a> concluded that SRY normally requires the 2 distinct NLS-dependent nuclear import pathways to reach sufficient levels in the nucleus for sex determination. The study documented cases of human disease that were explained, at a molecular level, by the impaired ability of a protein to accumulate in the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12764225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>46,XY True Hermaphroditism</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Braun, A., Kammerer, S., Cleve, H., Lohrs, U., Schwarz, H.-P., Kuhnle, U. <strong>True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case.</strong> Am. J. Hum. Genet. 52: 578-585, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8447323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8447323</a>]" pmid="8447323">Braun et al. (1993)</a> reported a 46,XY true hermaphrodite who had a mutation of SRY in gonadal DNA but not in leukocyte DNA, suggesting that the mutation was postzygotic. Because of this finding, <a href="#24" class="mim-tip-reference" title="Fuqua, J. S., McLaughlin, J., Perlman, E. J., Berkowitz, G. D. <strong>Analysis of the SRY gene in gonadal tissue of subjects with 46,XY gonadal dysgenesis (Letter)</strong> J. Clin. Endocr. Metab. 82: 701-702, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9024280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9024280</a>] [<a href="https://doi.org/10.1210/jcem.82.2.3771-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9024280">Fuqua et al. (1997)</a> attempted to determine whether postzygotic mutations of SRY might explain the numerous cases of gonadal dysgenesis in which no SRY mutation was detected in leukocyte DNA. They evaluated 16 subjects with 46,XY gonadal dysgenesis who had a normal SRY sequence in leukocyte DNA, 5 of them having 46,XY complete gonadal dysgenesis. They did not find mutations in gonadal DNA from any of 16 subjects and concluded that postzygotic mutations of SRY are a rare cause of 46,XY gonadal dysgenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9024280+8447323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#51" class="mim-tip-reference" title="Maier, E. M., Leitner, C., Lohrs, U., Kuhnle, U. <strong>True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene.</strong> J. Pediat. Endocr. Metab. 16: 575-580, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12793612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12793612</a>] [<a href="https://doi.org/10.1515/jpem.2003.16.4.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12793612">Maier et al. (2003)</a> reported a 46,XY true hermaphrodite who had a mutation in the SRY gene (<a href="#0006">480000.0006</a>). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. <a href="#51" class="mim-tip-reference" title="Maier, E. M., Leitner, C., Lohrs, U., Kuhnle, U. <strong>True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene.</strong> J. Pediat. Endocr. Metab. 16: 575-580, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12793612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12793612</a>] [<a href="https://doi.org/10.1515/jpem.2003.16.4.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12793612">Maier et al. (2003)</a> concluded that the mutated protein retained enough activity to allow normal development in some individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12793612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>46,XX Gonadal Dysgenesis, Complete or Partial</em></strong></p><p>
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<a href="#52" class="mim-tip-reference" title="Margarit, E., Coll, M. D., Oliva, R., Gomez, D., Soler, A., Ballesta, F. <strong>SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite.</strong> Am. J. Med. Genet. 90: 25-28, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602113</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000103)90:1<25::aid-ajmg5>3.0.co;2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10602113">Margarit et al. (2000)</a> studied a 46,XX true hermaphrodite and found that Yp-specific sequences, including the SRY gene, had been transferred to the long arm of one of the X chromosomes at the Xq28 level. The derivative X chromosome of the patient lacked q-telomeric sequences. The authors suggested that this was the first report of a Yp/Xq translocation. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences were missing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10602113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#66" class="mim-tip-reference" title="Sharp, A., Kusz, K., Jaruzelska, J., Tapper, W., Szarras-Czapnik, M., Wolski, J., Jacobs, P. <strong>Variability of sexual phenotype in 46,XX(SRY+) patients: the influence of spreading X inactivation versus position effects.</strong> J. Med. Genet. 42: 420-427, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863672</a>] [<a href="https://doi.org/10.1136/jmg.2004.022053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15863672">Sharp et al. (2005)</a> studied causes of incomplete masculinization in 15 individuals with segments of Yp translocated onto Xp. Expression studies showed little evidence for the spreading of X inactivation into Yp chromatin; however, in several cases, disruption of gene expression occurred independently of X inactivation, suggesting position effects resulting from chromosomal rearrangement. In particular, 5 of 6 translocation carriers with an intersex phenotype had either translocation breakpoints very close to SRY, or disrupted expression of genes near SRY in a manner unrelated to X inactivation. Southern blot analysis suggested the presence of a cryptic rearrangement 3 to 8 kb proximal to SRY in 1 case. <a href="#66" class="mim-tip-reference" title="Sharp, A., Kusz, K., Jaruzelska, J., Tapper, W., Szarras-Czapnik, M., Wolski, J., Jacobs, P. <strong>Variability of sexual phenotype in 46,XX(SRY+) patients: the influence of spreading X inactivation versus position effects.</strong> J. Med. Genet. 42: 420-427, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15863672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15863672</a>] [<a href="https://doi.org/10.1136/jmg.2004.022053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15863672">Sharp et al. (2005)</a> suggested that incomplete masculinization in cases of X/Y translocation is a result of disruption of normal SRY expression by position effects rather than X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15863672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#79" class="mim-tip-reference" title="Zenteno, J. C., Lopez, M., Vera, C., Mendez, J. P., Kofman-Alfaro, S. <strong>Two SRY-negative XX male brothers without genital ambiguity.</strong> Hum. Genet. 100: 606-610, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341880</a>] [<a href="https://doi.org/10.1007/s004390050561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341880">Zenteno et al. (1997)</a> described a Mexican family in which 2 brothers, aged 28 and 26, were thought to be instances of 'classic' XX males without genital ambiguity but were found to be negative for several Y-chromosome sequences, including SRY. The data suggested that an inherited loss-of-function mutation in a gene participating in the sex-determining cascade can induce normal male sexual differentiation in the absence of SRY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mosaicism</em></strong></p><p>
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<a href="#65" class="mim-tip-reference" title="Shahid, M., Dhillon, V. S., Aslam, M., Husain, S. A. <strong>Three new novel point mutations localized within and downstream of high-mobility group-box region in SRY gene in three Indian females with Turner syndrome.</strong> J. Clin. Endocr. Metab. 90: 2429-2435, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15687343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15687343</a>] [<a href="https://doi.org/10.1210/jc.2004-1110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15687343">Shahid et al. (2005)</a> performed molecular genetics studies in 3 Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Two patients carried mutations within the HMG box, and 1 patient carried a frameshift mutation downstream of the HMG box. The authors suggested that lack of a second sex chromosome in a majority of cells (mosaic karyotype and mutation in the SRY gene) in these patients may have triggered the short stature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15687343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Lange, J., Skaletsky, H., van Daalen, S. K. M., Embry, S. L., Korver, C. M., Brown, L. G., Oates, R. D., Silber, S., Repping, S., Page, D. C. <strong>Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes.</strong> Cell 138: 855-869, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19737515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19737515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19737515[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.cell.2009.07.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19737515">Lange et al. (2009)</a> identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. As expected, the 2 individuals carrying the idicYq chromosomes lacked the SRY gene and were phenotypic females; however, 18 of the 58 idicYp and isoYp individuals, who had 2 copies of SRY, were also 'sex-reversed' and raised as females or found in childhood to have 1 degenerate ovary and 1 testis. <a href="#48" class="mim-tip-reference" title="Lange, J., Skaletsky, H., van Daalen, S. K. M., Embry, S. L., Korver, C. M., Brown, L. G., Oates, R. D., Silber, S., Repping, S., Page, D. C. <strong>Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes.</strong> Cell 138: 855-869, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19737515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19737515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19737515[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.cell.2009.07.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19737515">Lange et al. (2009)</a> observed that the average intercentromeric distance in the feminized individuals was twice that in the males (p less than 10(-6)), supporting the hypothesis that mitotic instability and resultant XO mosaicism may cause sex reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19737515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a human SRY probe, <a href="#22" class="mim-tip-reference" title="Foster, J. W., Brennan, F. E., Hampikian, G. K., Goodfellow, P. N., Sinclair, A. H., Lovell-Badge, R., Selwood, L., Renfree, M. B., Cooper, D. W., Graves, J. A. M. <strong>Evolution of sex determination and the Y chromosome: SRY-related sequences in marsupials.</strong> Nature 359: 531-533, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1406969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1406969</a>] [<a href="https://doi.org/10.1038/359531a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1406969">Foster et al. (1992)</a> identified and cloned related genes from the Y chromosome of 2 marsupial species. Comparisons of eutherian ('placental') and metatherian (marsupial) Y-located SRY sequences suggested rapid evolution of these genes, especially outside the region encoding the DNA-binding 'high mobility group' domain (HMG box). The SRY homolog and the homolog of the mouse Ube1y were the first genes to be identified on the marsupial Y chromosome. <a href="#77" class="mim-tip-reference" title="Whitfield, L. S., Lovell-Badge, R., Goodfellow, P. N. <strong>Rapid sequence evolution of the mammalian sex-determining gene SRY.</strong> Nature 364: 713-715, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8355783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8355783</a>] [<a href="https://doi.org/10.1038/364713a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8355783">Whitfield et al. (1993)</a> and <a href="#70" class="mim-tip-reference" title="Tucker, P. K., Lundrigan, B. L. <strong>Rapid evolution of the sex determining locus in Old World mice and rats.</strong> Nature 364: 715-717, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8355784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8355784</a>] [<a href="https://doi.org/10.1038/364715a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8355784">Tucker and Lundrigan (1993)</a> likewise found that whereas the central 'high mobility group' domain of about 78 amino acids of the SRY protein is highly conserved, evolution in primates and in mice and rats has been rapid in the regions flanking the conserved domain. The high degree of sequence divergence and the frequency of nonsynonymous mutations suggested either that the majority of the coding sequence has no functional significance and therefore is not functionally constrained or that it has been subject to directional selection with species-specific adaptive divergence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8355783+8355784+1406969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#23" class="mim-tip-reference" title="Foster, J. W., Graves, J. A. M. <strong>An SRY-related sequence on the marsupial X chromosome: implications for the evolution of the mammalian testis-determining gene.</strong> Proc. Nat. Acad. Sci. 91: 1927-1931, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8127908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8127908</a>] [<a href="https://doi.org/10.1073/pnas.91.5.1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8127908">Foster and Graves (1994)</a> identified a sequence on the marsupial X chromosome that shares homology with SRY and shows near-identity with the mouse and human SOX3 gene (<a href="/entry/313430">313430</a>; formerly called a3), the SOX gene most closely related to SRY. <a href="#23" class="mim-tip-reference" title="Foster, J. W., Graves, J. A. M. <strong>An SRY-related sequence on the marsupial X chromosome: implications for the evolution of the mammalian testis-determining gene.</strong> Proc. Nat. Acad. Sci. 91: 1927-1931, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8127908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8127908</a>] [<a href="https://doi.org/10.1073/pnas.91.5.1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8127908">Foster and Graves (1994)</a> suggested that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining SRY gene was derived. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8127908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 therian mammals (placentals and marsupials), sex is determined by an XX female:XY male system in which the SRY gene on the Y chromosome affects male determination. Birds have a ZW female:ZZ male system with no homology with mammalian sex chromosomes. In birds, dosage of a Z-borne gene, possibly DMRT1 (<a href="/entry/602424">602424</a>), affects male determination. Platypus employ a sex-determining system of 5 X and 5 Y chromosomes. Females have 2 copies of the 5 Xs; males have 5X and 5Y chromosomes, which form an alternating XY chain during male meiosis. <a href="#74" class="mim-tip-reference" title="Veyrunes, F., Waters, P. D., Miethke, P., Rens, W., McMillan, D., Alsop, A. E., Grutzner, F., Deakin, J. E., Whittington, C. M., Schatzkamer, K., Kremitzki, C. L., Graves, T., Ferguson-Smith, M. A., Warren, W., Graves, J. A. M. <strong>Bird-like sex chromosomes of platypus imply recent origin of mammal sex chromosomes.</strong> Genome Res. 18: 965-973, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18463302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18463302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18463302[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/10.1101/gr.7101908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18463302">Veyrunes et al. (2008)</a> found no homology between the 10 platypus sex chromosomes and the ancestral therian X chromosome, which is homologous to platypus chromosome 6. Orthologs of genes in the conserved region of human X (including SOX3, the gene from which SRY evolved) all map to platypus chromosome 6, which therefore represents the ancestral autosome from which the therian X and Y pair derived. The platypus X chromosomes have substantial homology with the bird Z chromosome (including DMRT1), and to segments syntenic with this region in the human genome. <a href="#74" class="mim-tip-reference" title="Veyrunes, F., Waters, P. D., Miethke, P., Rens, W., McMillan, D., Alsop, A. E., Grutzner, F., Deakin, J. E., Whittington, C. M., Schatzkamer, K., Kremitzki, C. L., Graves, T., Ferguson-Smith, M. A., Warren, W., Graves, J. A. M. <strong>Bird-like sex chromosomes of platypus imply recent origin of mammal sex chromosomes.</strong> Genome Res. 18: 965-973, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18463302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18463302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18463302[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/10.1101/gr.7101908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18463302">Veyrunes et al. (2008)</a> concluded that the therian X and Y chromosomes, including the SRY gene, evolved from an autosomal pair after the divergence of monotremes only 166 million years ago. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18463302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hughes, J. F., Skaletsky, H., Pyntikova, T., Graves, T. A., van Daalen, S. K. M., Minx, P. J., Fulton, R. S., McGrath, S. D., Locke, D. P., Friedman, C., Trask, B. J., Mardis, E. R., Warren, W. C., Repping, S., Rozen, S., Wilson, R. K., Page, D. C. <strong>Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content.</strong> Nature 463: 536-539, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20072128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20072128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20072128[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/nature08700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20072128">Hughes et al. (2010)</a> finished sequencing the male-specific region of the Y chromosome (MSY) in chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. Comparison of the MSYs of the 2 species showed that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. <a href="#36" class="mim-tip-reference" title="Hughes, J. F., Skaletsky, H., Pyntikova, T., Graves, T. A., van Daalen, S. K. M., Minx, P. J., Fulton, R. S., McGrath, S. D., Locke, D. P., Friedman, C., Trask, B. J., Mardis, E. R., Warren, W. C., Repping, S., Rozen, S., Wilson, R. K., Page, D. C. <strong>Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content.</strong> Nature 463: 536-539, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20072128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20072128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20072128[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/nature08700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20072128">Hughes et al. (2010)</a> suggested that the extraordinary divergence of the chimpanzee and human MSYs was driven by 4 synergistic factors: the prominent role of the MSY in sperm production, 'genetic hitchhiking' effects in the absence of meiotic crossingover, frequent ectopic recombination within the MSY, and species differences in mating behavior. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20072128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The human and mouse Sry genes share 89% amino acid identity in their HMG box domains, but they diverge significantly in their C termini. <a href="#14" class="mim-tip-reference" title="Coward, P., Nagai, K., Chen, D., Thomas, H. D., Nagamine, C. M., Lau, Y.-F. C. <strong>Polymorphism of a CAG trinucleotide repeat within Sry correlates with B6.Y-Dom sex reversal.</strong> Nature Genet. 6: 245-250, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8012385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8012385</a>] [<a href="https://doi.org/10.1038/ng0394-245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8012385">Coward et al. (1994)</a> found that Sry alleles from all mouse strains examined encode a glutamine- and histidine-rich C-terminal domain. Sry alleles encoding a polyglutamine tract of either 13 or 11 glutamine residues were associated with partial (fetal) or complete sex reversal, respectively, when introduced on a C57BL/6J background. Alleles encoding a tract of 12 glutamine residues were not associated with sex reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8012385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Only the HMG box region of the SRY gene has been conserved through evolution, suggesting that SRY function depends solely on the HMG box and therefore acts as an architectural transcription factor. In mice, SRY includes a large CAG trinucleotide repeat region encoding a C-terminal glutamine-rich domain that acts as a transcriptional trans-activator in vitro. The absence of this or any other potential trans-activating domain in other mammals, however, has raised doubts as to its biologic relevance. To test directly whether the glutamine-rich region is required for SRY function in vivo <a href="#6" class="mim-tip-reference" title="Bowles, J., Cooper, L., Berkman, J., Koopman, P. <strong>Sry requires a CAG repeat domain for male sex determination in Mus musculus.</strong> Nature Genet. 22: 405-408, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10431249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10431249</a>] [<a href="https://doi.org/10.1038/11981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10431249">Bowles et al. (1999)</a> created truncation mutations of the Mus musculus SRY gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay. SRY constructs that encoded proteins lacking a glutamine-rich region were unable to effect male sex determination, in contrast to their wildtype counterparts. <a href="#6" class="mim-tip-reference" title="Bowles, J., Cooper, L., Berkman, J., Koopman, P. <strong>Sry requires a CAG repeat domain for male sex determination in Mus musculus.</strong> Nature Genet. 22: 405-408, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10431249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10431249</a>] [<a href="https://doi.org/10.1038/11981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10431249">Bowles et al. (1999)</a> concluded that the glutamine-rich repeat domain of the mouse SRY protein has an essential role in sex determination in vivo and that SRY may act via a fundamentally different biochemical mechanism in mice compared with other mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10431249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Nef, S., Verma-Kurvari, S., Merenmies, J., Vassalli, J.-D., Efstratiadis, A., Accili, D., Parada, L. F. <strong>Testis determination requires insulin receptor family function in mice.</strong> Nature 426: 291-295, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628051</a>] [<a href="https://doi.org/10.1038/nature02059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628051">Nef et al. (2003)</a> demonstrated that the insulin receptor tyrosine kinase family, comprising INSR (<a href="/entry/147670">147670</a>), IGF1R (<a href="/entry/147370">147370</a>), and IRR (<a href="/entry/147671">147671</a>), is required for the appearance of male gonads and thus for male sexual differentiation in mice. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry and the early testis-specific marker Sox9 (<a href="/entry/608160">608160</a>) indicated that the insulin signaling pathway is required for male sex determination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 6 sterile heifers that were female in appearance and in genital organs, <a href="#43" class="mim-tip-reference" title="Kawakura, K., Miyake, Y.-I., Murakami, R.-K., Kondoh, S., Hirata, T.-I., Kaneda, Y. <strong>Deletion of the SRY region on the Y chromosome detected in bovine gonadal hypoplasia (XY female) by PCR.</strong> Cytogenet. Cell Genet. 72: 183-184, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978769</a>] [<a href="https://doi.org/10.1159/000134182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978769">Kawakura et al. (1996)</a> found that blood, skin, spleen, and kidney showed a normal male 60,XY karyotype. Although the SRY gene was detected by PCR in normal bull, it was not detected in normal cow or in 3 60,XY female bovine cases studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8978769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 transcription activator-like effector nuclease (TALEN) technology, <a href="#42" class="mim-tip-reference" title="Kato, T., Miyata, K., Sonobe, M., Yamashita, S., Tamano, M., Miura, K., Kanai, Y., Miyamoto, S., Sakuma, T., Yamamoto, T., Inui, M., Kikusui, T., Asahara, H., Takada, S. <strong>Production of Sry knockout mouse using TALEN via oocyte injection.</strong> Sci. Rep. 3: 3136, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24190364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24190364</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24190364[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/srep03136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24190364">Kato et al. (2013)</a> created an Sry-knockout XY mouse, which displayed sex reversal. The knockout mice had female external and internal genitalia, wildtype female levels of blood testosterone, and largely female sexually dimorphic nucleus of medial preoptic area of the brain. Mutant mice exhibited a slightly lengthened estrous cycle and performed copulatory behavior as females, although they appeared to be infertile. Ovaries of the mutant mice had fewer developing follicles and were more luteinized that those of wildtype females, which may account for infertility in the Sry-knockout mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24190364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#55" class="mim-tip-reference" title="Miyawaki, S., Kuroki, S., Maeda, R., Okashita, N., Koopman, P., Tachibana, M. <strong>The mouse Sry locus harbors a cryptic exon that is essential for male sex determination.</strong> Science 370: 121-124, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004521</a>] [<a href="https://doi.org/10.1126/science.abb6430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004521">Miyawaki et al. (2020)</a> identified a cryptic second exon in the mouse Sry gene and a corresponding 2-exon Sry transcript that they designated SryT. XY mice lacking SryT only were sex-reversed, and ectopic expression of SryT in XX mice induced male development. SryT mRNA was expressed similarly to that of the canonical single-exon Sry transcript, which the authors called SryS, but the SryT protein was expressed predominantly due to the absence of a degron found at the C terminus of SryS. Sry exon 2 appeared to have evolved recently in mice through acquisition of a retrotransposon-derived coding sequence to replace the degron. <a href="#55" class="mim-tip-reference" title="Miyawaki, S., Kuroki, S., Maeda, R., Okashita, N., Koopman, P., Tachibana, M. <strong>The mouse Sry locus harbors a cryptic exon that is essential for male sex determination.</strong> Science 370: 121-124, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33004521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33004521</a>] [<a href="https://doi.org/10.1126/science.abb6430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33004521">Miyawaki et al. (2020)</a> concluded that, in nature, SryT, and not SryS, is the bona fide testis-determining factor in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33004521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>DNA-binding proteins are typically involved in the developmental control of gene expression. High mobility group (HMG) proteins contain a DNA-binding motif called the HMG domain. They have been proposed to act either as target-specific transcription factors or as chromatin structure regulatory elements, or both. <a href="#40" class="mim-tip-reference" title="Jay, P., Sahly, I., Goze, C., Taviaux, S., Poulat, F., Couly, G., Abitbol, M., Berta, P. <strong>SOX22 is a new member of the SOX gene family, mainly expressed in human nervous tissue.</strong> Hum. Molec. Genet. 6: 1069-1077, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9215677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9215677</a>] [<a href="https://doi.org/10.1093/hmg/6.7.1069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9215677">Jay et al. (1997)</a> stated that more than 100 HMG-box containing proteins have been reported and classified into 2 distinct subgroups according to the sequence specificity of the DNA binding, the number of HMG DNA-binding domains, and phylogenetic considerations. The first subgroup comprises proteins that are all potential transcription factors believed to control gene expression during development. They contain only 1 DNA-binding domain and they bind to DNA in a sequence-specific fashion. The second subgroup consists of all other HMG box-containing proteins, most of which contain more than 1 DNA-binding domain and can bind to DNA in a non-sequence-specific manner. SRY belongs to the first subgroup. Its cloning led to the discovery of a family of both autosomal and X-linked genes called SOX (for 'SRY-box' related) because of the strong homology of their DNA-binding domain with the HMG box of SRY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9215677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Page, D. C., Mosher, R., Simpson, E. M., Fisher, E. M. C., Mardon, G., Pollack, J., McGillivray, B., de la Chapelle, A., Brown, L. G. <strong>The sex-determining region of the human Y chromosome encodes a finger protein.</strong> Cell 51: 1091-1104, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3690661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3690661</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90595-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3690661">Page et al. (1987)</a> cloned part or all of what they thought to be the TDF gene, found that some sequences were highly conserved in mammals and even birds, and showed that the nucleotide sequence of the conserved DNA codes for zinc finger domains. ZFY (zinc finger protein, Y-linked; <a href="/entry/314980">314980</a>) was the designation approved by the HGM workshop committee, with ZFX being the X-linked counterpart. ZFY proved, however, not to be TDF (<a href="#59" class="mim-tip-reference" title="Palmer, M. S., Sinclair, A. H., Berta, P., Ellis, N. A., Goodfellow, P. N., Abbas, N. E., Fellous, M. <strong>Genetic evidence that ZFY is not the testis-determining factor.</strong> Nature 342: 937-939, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594087</a>] [<a href="https://doi.org/10.1038/342937a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594087">Palmer et al., 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3690661+2594087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=480000[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231178 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231178;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=rs606231178" 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=rs606231178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#38" class="mim-tip-reference" title="Jager, R. J., Anvret, M., Hall, K., Scherer, G. <strong>A human XY female with a frame shift mutation in the candidate testis-determining gene SRY.</strong> Nature 348: 452-454, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2247151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2247151</a>] [<a href="https://doi.org/10.1038/348452a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2247151">Jager et al. (1990)</a> demonstrated a mutation in SRY in 1 of 12 sex-reversed XY females with gonadal dysgenesis (SRXY1; <a href="/entry/400044">400044</a>) who had no large deletions of the short arm of the Y chromosome. They found a 4-bp deletion (nucleotides 773-776) in the part of the SRY gene that encodes a conserved DNA-binding motif. A frameshift presumably led to a nonfunctional protein. Mutation occurred de novo, because the father had a normal SRY sequence. This provided strong evidence that SRY is TDF. The de novo G-to-A mutation led to a change from methionine to isoleucine. <a href="#34" class="mim-tip-reference" title="Hawkins, J. R. <strong>Mutational analysis of SRY in XY females.</strong> Hum. Mutat. 2: 347-350, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8257986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8257986</a>] [<a href="https://doi.org/10.1002/humu.1380020504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8257986">Hawkins (1993)</a> noted that the mutation is in the HMG box of SRY. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8257986+2247151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894956;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=rs104894956" 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=rs104894956" 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=RCV000010391" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010391" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010391</a>
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<p>In an XY female with gonadal dysgenesis (SRXY1; <a href="/entry/400044">400044</a>), her father, her 2 brothers and an uncle, <a href="#39" class="mim-tip-reference" title="Jager, R. J., Harley, V. R., Pfeiffer, R. A., Goodfellow, P. N., Scherer, G. <strong>A familial mutation in the testis-determining gene SRY shared by both sexes.</strong> Hum. Genet. 90: 350-355, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1483689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1483689</a>] [<a href="https://doi.org/10.1007/BF00220457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1483689">Jager et al. (1992)</a> found a T-to-C transition in the region of the SRY gene coding for a protein motif known as the high mobility group (HMG) box, a protein domain known to confer DNA-binding specificity on the SRY protein. The mutation resulted in the substitution, at amino acid position 109, of a serine residue for phenylalanine, a conserved aromatic residue in almost all HMG box motifs known. This F109S mutation was not found in 176 male controls. When recombinant wildtype SRY and SRY(F109S) mutant protein were tested in vitro for binding to the target site AAC AAAG, no differences in DNA-binding activity were observed. These results implied that the F109S mutation either is a rare neutral sequence variant, or produces an SRY protein with slightly altered in vivo activity, the resulting sex phenotype depending on the genetic background or environmental factors. The proband had primary amenorrhea and was 180 cm tall. Prior to therapy, mammary development was at stage III (Tanner). No signs of virilization were found. At laparotomy, bilateral streak gonads, atrophic fallopian tubes, and a rudimentary uterus with a narrow lumen were detected. Although the paternal uncle with the F109S mutation had an undescended right testis, the family was unremarkable with regard to infertility, gynecologic tumors, and abnormal sex phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1483689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894957 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894957;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=rs104894957" 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=rs104894957" 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=RCV000010392 OR RCV002460889" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010392, RCV002460889" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010392...</a>
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<p><a href="#75" class="mim-tip-reference" title="Vilain, E., McElreavey, K., Jaubert, F., Raymond, J.-P., Richaud, F., Fellous, M. <strong>Familial case with sequence variant in the testis-determining region associated with two sex phenotypes.</strong> Am. J. Hum. Genet. 50: 1008-1011, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570829</a>]" pmid="1570829">Vilain et al. (1992)</a> described a family in which all 5 XY individuals in 2 generations had a single basepair substitution resulting in an amino acid change in the conserved domain of the SRY open reading frame. A G-to-C transversion at nucleotide 588 resulted in substitution of leucine for valine-60. Three of the individuals were XY sex-reversed females (SRXY1; <a href="/entry/400044">400044</a>) and 2 were XY males. One of the males had 8 children; all were phenotypic females, including 2 who were sex-reversed XY females carrying the mutation mentioned. Several models were proposed to explain association between a sequence variant in SRY and 2 alternative sex phenotypes. These explanations included the existence of alleles at an unlinked locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1570829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894958;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=rs104894958" 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=rs104894958" 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=RCV000010393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010393</a>
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<p><a href="#53" class="mim-tip-reference" title="McElreavey, K. D., Vilain, E., Boucekkine, C., Vidaud, M., Jaubert, F., Richaud, F., Fellous, M. <strong>XY sex reversal associated with a nonsense mutation in SRY.</strong> Genomics 13: 838-840, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639410</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90164-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1639410">McElreavey et al. (1992)</a> described an XY sex-reversed female with pure gonadal dysgenesis (SRXY1; <a href="/entry/400044">400044</a>) who harbored a de novo nonsense mutation in SRY, which resulted directly in the formation of a stop codon in the putative DNA-binding motif. A C-to-T transition at nucleotide 687 changed a glutamine codon (CAG) to a termination codon (TAG). The patient, referred to by the authors as the 'propositus,' was a phenotypic female who presented at age 20 years for primary amenorrhea. Treatment with estrogen induced menstruation and slight enlargement of the breasts which were underdeveloped. Laparotomy showed 2 streak gonads without germ cells or remnants of tubes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs104894959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894959;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/rs104894959?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=rs104894959" 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=rs104894959" 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=RCV000010394 OR RCV000010395" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010394, RCV000010395" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010394...</a>
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<p>In 'patient 213' (patient 4 in the report of <a href="#4" class="mim-tip-reference" title="Berkovitz, G. D., Fechner, P. Y., Zacur, H. W., Rock, J. A., Snyder, H. M., III, Migeon, C. J., Perlman, E. J. <strong>Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation.</strong> Medicine 70: 375-383, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1956279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1956279</a>] [<a href="https://doi.org/10.1097/00005792-199111000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1956279">Berkovitz et al., 1991</a>), a phenotypic female with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; <a href="/entry/400044">400044</a>), <a href="#33" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Goodfellow, P. N., Migeon, C. J., Smith, K. D., Berkovitz, G. D. <strong>Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis.</strong> Am. J. Hum. Genet. 51: 979-984, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415266</a>]" pmid="1415266">Hawkins et al. (1992)</a> identified a C-G transversion at nucleotide 680, causing an isoleucine-to-methionine amino acid substitution within the HMG box. The father and brother of patient 213 also carried the mutation, which was not found in 78 ethnically matched unrelated males. The authors noted that in vitro studies by <a href="#30" class="mim-tip-reference" title="Harley, V. R., Jackson, D. I., Hextall, P. J., Hawkins, J. R., Berkovitz, G. D., Sockanathan, S., Lovell-Badge, R., Goodfellow, P. N. <strong>DNA binding activity of recombinant SRY from normal males and XY females.</strong> Science 255: 453-456, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734522</a>] [<a href="https://doi.org/10.1126/science.1734522" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1734522">Harley et al. (1992)</a> demonstrated that the I90M mutant had reduced DNA-binding activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1956279+1734522+1415266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Dork, T., Stuhrmann, M., Miller, K., Schmidtke, J. <strong>Independent observation of SRY mutation I90M in a patient with complete gonadal dysgenesis. (Letter)</strong> Hum. Mutat. 11: 90-91, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450909</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:1<90::AID-HUMU14>3.0.CO;2-U" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9450909">Dork et al. (1998)</a> observed this mutation in a patient unrelated to that reported by <a href="#33" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Goodfellow, P. N., Migeon, C. J., Smith, K. D., Berkovitz, G. D. <strong>Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis.</strong> Am. J. Hum. Genet. 51: 979-984, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415266</a>]" pmid="1415266">Hawkins et al. (1992)</a>. None of the previously reviewed mutations had been observed in more than a single family. In 3 cases, however, fertile fathers were found to share the same SRY mutation with their sex-reversed daughters (<a href="#5" class="mim-tip-reference" title="Berta, P., Hawkins, J. R., Sinclair, A. H., Taylor, A., Griffiths, B. L., Goodfellow, P. N., Fellous, M. <strong>Genetic evidence equating SRY and the testis-determining factor.</strong> Nature 348: 448-450, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2247149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2247149</a>] [<a href="https://doi.org/10.1038/348448A0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2247149">Berta et al., 1990</a>; <a href="#39" class="mim-tip-reference" title="Jager, R. J., Harley, V. R., Pfeiffer, R. A., Goodfellow, P. N., Scherer, G. <strong>A familial mutation in the testis-determining gene SRY shared by both sexes.</strong> Hum. Genet. 90: 350-355, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1483689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1483689</a>] [<a href="https://doi.org/10.1007/BF00220457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1483689">Jager et al., 1992</a>; <a href="#75" class="mim-tip-reference" title="Vilain, E., McElreavey, K., Jaubert, F., Raymond, J.-P., Richaud, F., Fellous, M. <strong>Familial case with sequence variant in the testis-determining region associated with two sex phenotypes.</strong> Am. J. Hum. Genet. 50: 1008-1011, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570829</a>]" pmid="1570829">Vilain et al., 1992</a>). In the absence of mosaicism, there are plausible explanations for these familiar variants. The variant could fortuitously occur in a family segregating for a different sex-reversing gene, or the variant may predispose toward sex reversal and cause a differentiation effect only in association with other genetic or environmental factors. In the case reported by <a href="#33" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Goodfellow, P. N., Migeon, C. J., Smith, K. D., Berkovitz, G. D. <strong>Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis.</strong> Am. J. Hum. Genet. 51: 979-984, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415266</a>]" pmid="1415266">Hawkins et al. (1992)</a>, I90M was likewise associated with complete gonadal dysgenesis in the proband but was also present in normal relatives of the patient, including the father. Thus, <a href="#18" class="mim-tip-reference" title="Dork, T., Stuhrmann, M., Miller, K., Schmidtke, J. <strong>Independent observation of SRY mutation I90M in a patient with complete gonadal dysgenesis. (Letter)</strong> Hum. Mutat. 11: 90-91, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450909</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:1<90::AID-HUMU14>3.0.CO;2-U" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9450909">Dork et al. (1998)</a> concluded that this appears to be an instance of a Y-linked inherited disorder with incomplete penetrance and suggested that identification of unrelated individuals carrying the I90M mutation may help to elucidate the mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1570829+1415266+2247149+9450909+1483689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#51" class="mim-tip-reference" title="Maier, E. M., Leitner, C., Lohrs, U., Kuhnle, U. <strong>True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene.</strong> J. Pediat. Endocr. Metab. 16: 575-580, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12793612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12793612</a>] [<a href="https://doi.org/10.1515/jpem.2003.16.4.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12793612">Maier et al. (2003)</a> reported a 46,XY true hermaphrodite (see <a href="/entry/400044">400044</a>) who had the I90M mutation in the SRY gene. The father, 3 uncles, and an older brother carried the identical mutation without phenotypic effects. <a href="#51" class="mim-tip-reference" title="Maier, E. M., Leitner, C., Lohrs, U., Kuhnle, U. <strong>True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene.</strong> J. Pediat. Endocr. Metab. 16: 575-580, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12793612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12793612</a>] [<a href="https://doi.org/10.1515/jpem.2003.16.4.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12793612">Maier et al. (2003)</a> concluded that the mutated protein retained enough activity to allow normal development in some individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12793612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894964 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894964;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=rs104894964" 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=rs104894964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In their 'patient 207' (patient 5 of <a href="#4" class="mim-tip-reference" title="Berkovitz, G. D., Fechner, P. Y., Zacur, H. W., Rock, J. A., Snyder, H. M., III, Migeon, C. J., Perlman, E. J. <strong>Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation.</strong> Medicine 70: 375-383, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1956279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1956279</a>] [<a href="https://doi.org/10.1097/00005792-199111000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1956279">Berkovitz et al., 1991</a>) with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; <a href="/entry/400044">400044</a>), <a href="#33" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Goodfellow, P. N., Migeon, C. J., Smith, K. D., Berkovitz, G. D. <strong>Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis.</strong> Am. J. Hum. Genet. 51: 979-984, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415266</a>]" pmid="1415266">Hawkins et al. (1992)</a> identified an A-T transversion at nucleotide 727, resulting in a lysine-to-isoleucine substitution within the HMG box. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1956279+1415266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000010397" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010397" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010397</a>
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<p>In their 'patient 208' (patient 6 of <a href="#4" class="mim-tip-reference" title="Berkovitz, G. D., Fechner, P. Y., Zacur, H. W., Rock, J. A., Snyder, H. M., III, Migeon, C. J., Perlman, E. J. <strong>Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation.</strong> Medicine 70: 375-383, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1956279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1956279</a>] [<a href="https://doi.org/10.1097/00005792-199111000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1956279">Berkovitz et al., 1991</a>) with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; <a href="/entry/400044">400044</a>), <a href="#33" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Goodfellow, P. N., Migeon, C. J., Smith, K. D., Berkovitz, G. D. <strong>Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis.</strong> Am. J. Hum. Genet. 51: 979-984, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415266</a>]" pmid="1415266">Hawkins et al. (1992)</a> found deletion of nucleotide 734 causing a frameshift. The father and brother of patient 208 did not share the deletion, indicating that the mutation was de novo. <a href="#34" class="mim-tip-reference" title="Hawkins, J. R. <strong>Mutational analysis of SRY in XY females.</strong> Hum. Mutat. 2: 347-350, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8257986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8257986</a>] [<a href="https://doi.org/10.1002/humu.1380020504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8257986">Hawkins (1993)</a> noted that the mutation is in the HMG box of SRY. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1956279+8257986+1415266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 46,XY SEX REVERSAL 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">rs104894966 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894966;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=rs104894966" 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=rs104894966" 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=RCV000010398" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010398" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010398</a>
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<p>In a Chinese XY female with gonadal dysgenesis described as Swyer syndrome (SRXY1; <a href="/entry/400044">400044</a>), <a href="#78" class="mim-tip-reference" title="Zeng, Y., Ren, Z., Zhang, M., Huang, Y., Zeng, F., Huang, S. <strong>A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis.</strong> J. Med. Genet. 30: 655-657, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8105086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8105086</a>] [<a href="https://doi.org/10.1136/jmg.30.8.655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8105086">Zeng et al. (1993)</a> described a G-to-A transition in codon 113 resulting in a change from alanine to threonine. This residue lies within the putative DNA binding motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8105086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 46,XY SEX REVERSAL 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">rs104894967 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894967;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=rs104894967" 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=rs104894967" 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=RCV000010399" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010399" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010399</a>
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<p><a href="#37" class="mim-tip-reference" title="Iida, T., Nakahori, Y., Komaki, R., Mori, E., Hayashi, N., Tsutsumi, O., Taketani, Y., Nakagome, Y. <strong>A novel missense mutation in the HMG box of the SRY gene in a patient with XY sex reversal.</strong> Hum. Molec. Genet. 3: 1437-1438, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987333</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987333">Iida et al. (1994)</a> identified a single-basepair substitution within the HMG box of the SRY gene in a 28-year-old married Japanese woman with a history of primary amenorrhea and infertility. Physical examination showed an apparently normal female with a weight of 62 kg and a height of 170.5 cm. While the external genitalia were those of a female, they were infantile with no hypertrophy of the clitoris. The vagina was normal and a cervix was present. The uterus was normal in shape and position. Laboratory examination demonstrated that the amenorrhea was due to ovarian failure. There was no elevation of androgen levels. The karyotype was 46,XY (SRXY1; <a href="/entry/400044">400044</a>). Both gonads were partially resected because of the risk of malignant development and showed fibroadipose tissue with no malignant cells and no ovarian or testicular components. By single-strand conformation polymorphism analysis followed by direct sequencing, <a href="#37" class="mim-tip-reference" title="Iida, T., Nakahori, Y., Komaki, R., Mori, E., Hayashi, N., Tsutsumi, O., Taketani, Y., Nakagome, Y. <strong>A novel missense mutation in the HMG box of the SRY gene in a patient with XY sex reversal.</strong> Hum. Molec. Genet. 3: 1437-1438, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987333</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987333">Iida et al. (1994)</a> demonstrated a GGT to GAT substitution in codon 107, counted from the initiation site of the gene, which predicted a change from a tryptophan residue to a termination codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 46,XY SEX REVERSAL 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">rs104894968 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894968;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=rs104894968" 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=rs104894968" 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=RCV000010400" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010400" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010400</a>
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<p>This mutation, which caused sex reversal in a female patient with a 46,XY karyotype (SRXY1; <a href="/entry/400044">400044</a>), was used by <a href="#29" class="mim-tip-reference" title="Haqq, C. M., King, C.-Y., Ukiyama, E., Falsafi, S., Haqq, T. N., Donahoe, P. K., Weiss, M. A. <strong>Molecular basis of mammalian sexual determination: activation of mullerian inhibiting substance gene expression by SRY.</strong> Science 266: 1494-1500, 1994. Note: Erratum: Science 267: 317 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7985018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7985018</a>] [<a href="https://doi.org/10.1126/science.7985018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7985018">Haqq et al. (1994)</a> to demonstrate that the structural interactions of the HMG box with DNA was altered to result in failure to induce transcription of the gene for mullerian inhibiting substance. The normal protein-DNA interaction consists of partial side chain intercalation into a widened minor groove. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7985018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Studying this same mutation, <a href="#60" class="mim-tip-reference" title="Peters, R., King, C.-Y., Ukiyama, E., Falsafi, S., Donahoe, P. K., Weiss, M. A. <strong>An SRY mutation causing human sex reversal resolves a general mechanism of structure-specific DNA recognition: application to the four-way DNA junction.</strong> Biochemistry 34: 4569-4576, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7718558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7718558</a>] [<a href="https://doi.org/10.1021/bi00014a009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7718558">Peters et al. (1995)</a> demonstrated that 2 DNA-binding activities of SRY could be distinguished. The sequence-specific recognition of duplex DNA must be required for male sex determination because it was eliminated by this mutation in the SRY HMG box. However, the sequence-independent binding to the sharp angles of 4-way DNA junctions was not affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7718558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 46,XY SEX REVERSAL 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">rs104894969 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894969;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=rs104894969" 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=rs104894969" 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=RCV000010401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010401</a>
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<p>In an XY female (SRXY1; <a href="/entry/400044">400044</a>), <a href="#5" class="mim-tip-reference" title="Berta, P., Hawkins, J. R., Sinclair, A. H., Taylor, A., Griffiths, B. L., Goodfellow, P. N., Fellous, M. <strong>Genetic evidence equating SRY and the testis-determining factor.</strong> Nature 348: 448-450, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2247149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2247149</a>] [<a href="https://doi.org/10.1038/348448A0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2247149">Berta et al. (1990)</a> identified a G-to-A transition in the SRY gene resulting in a change from methionine-64 to isoleucine. This residue lies within the HMG box. The mutation was presumed to be de novo because it was not found in the patient's father or brother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2247149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 46,XY SEX REVERSAL 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">rs104894965 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894965;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=rs104894965" 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=rs104894965" 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=RCV000010402" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010402" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010402</a>
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<p>In an XY female (SRXY1; <a href="/entry/400044">400044</a>), <a href="#32" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Berta, P., Levilliers, J., Van der Auwera, B., Goodfellow, P. N. <strong>Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal.</strong> Hum. Genet. 88: 471-474, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1339396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1339396</a>] [<a href="https://doi.org/10.1007/BF00215684" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1339396">Hawkins et al. (1992)</a> identified a G-to-A transition at codon 70 of SRY which results in a stop codon at trp70. This residue lies within the HMG box. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1339396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0014" class="mim-anchor"></a>
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<strong>.0014 MOVED TO <a href="/entry/480000#0006">480000.0006</a></strong>
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<a id="0015" class="mim-anchor"></a>
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<strong>.0015 46,XY SEX REVERSAL 1</strong>
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SRY, LYS92TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894970 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894970;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=rs104894970" 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=rs104894970" 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=RCV000010403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010403</a>
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<p>In an XY female (SRXY1; <a href="/entry/400044">400044</a>), <a href="#56" class="mim-tip-reference" title="Muller, J., Schwartz, M., Skakkebaek, N. E. <strong>Analysis of the sex-determining region of the Y-chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46,XY female.</strong> J. Clin. Endocr. Metab. 75: 331-333, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1619028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1619028</a>] [<a href="https://doi.org/10.1210/jcem.75.1.1619028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1619028">Muller et al. (1992)</a> identified an A-to-T transversion at codon 92 of the SRY gene which results in a stop codon at lys92. This residue lies within the HMG box. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1619028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<h4>
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<span class="mim-font">
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<strong>.0016 46,XY SEX REVERSAL 1</strong>
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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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SRY, GLY95ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894974 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894974;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=rs104894974" 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=rs104894974" 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=RCV000010404" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010404" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010404</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 an XY female (SRXY1; <a href="/entry/400044">400044</a>), <a href="#32" class="mim-tip-reference" title="Hawkins, J. R., Taylor, A., Berta, P., Levilliers, J., Van der Auwera, B., Goodfellow, P. N. <strong>Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal.</strong> Hum. Genet. 88: 471-474, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1339396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1339396</a>] [<a href="https://doi.org/10.1007/BF00215684" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1339396">Hawkins et al. (1992)</a> identified a G-to-C transversion resulting in a change from glycine-95 to arginine. This residue lies within the HMG box. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1339396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MOVED TO <a href="/entry/480000#0007">480000.0007</a></strong>
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</span>
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</h4>
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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 46,XY SEX REVERSAL 1</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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SRY, TYR4TER
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894975 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894975;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=rs104894975" 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=rs104894975" 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=RCV000010405" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010405" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010405</a>
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</span>
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<span class="mim-text-font">
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<p><a href="#73" class="mim-tip-reference" title="Veitia, R., Ion, A., Barbaux, S., Jobling, M. A., Souleyreau, N., Ennis, K., Ostrer, H., Tosi, M., Meo, T., Chibani, J., Fellous, M., McElreavey, K. <strong>Mutations and sequence variants in the testis-determining region of the Y chromosome in individuals with a 46,XY female phenotype.</strong> Hum. Genet. 99: 648-652, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150734</a>] [<a href="https://doi.org/10.1007/s004390050422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150734">Veitia et al. (1997)</a> reported a T-to-A transversion occurring at nucleotide 12 in the SRY gene, resulting in a premature termination codon prior to the HMG box. This was a de novo substitution in a completely sex-reversed patient (SRXY1; <a href="/entry/400044">400044</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 46,XY SEX REVERSAL 1</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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SRY, ARG133TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894976 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894976;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=rs104894976" 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=rs104894976" 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=RCV000010406" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010406" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010406</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><a href="#73" class="mim-tip-reference" title="Veitia, R., Ion, A., Barbaux, S., Jobling, M. A., Souleyreau, N., Ennis, K., Ostrer, H., Tosi, M., Meo, T., Chibani, J., Fellous, M., McElreavey, K. <strong>Mutations and sequence variants in the testis-determining region of the Y chromosome in individuals with a 46,XY female phenotype.</strong> Hum. Genet. 99: 648-652, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150734</a>] [<a href="https://doi.org/10.1007/s004390050422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150734">Veitia et al. (1997)</a> found a de novo recurrence of the C-to-T transition which gave rise to the arg133trp mutation first reported by <a href="#1" class="mim-tip-reference" title="Affara, N. A., Chalmers, I. J., Ferguson-Smith, M. A. <strong>Analysis of the SRY gene in 22 sex-reversed XY females identifies four new point mutations in the conserved DNA binding domain.</strong> Hum. Molec. Genet. 2: 785-789, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8353496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8353496</a>] [<a href="https://doi.org/10.1093/hmg/2.6.785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8353496">Affara et al. (1993)</a>. Both patients had pure gonadal dysgenesis (SRXY1; <a href="/entry/400044">400044</a>). The arg at codon 133 was conserved in the SRY gene of all species studied at that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9150734+8353496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<a id="0020" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0020 46,XY SEX REVERSAL 1</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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SRY, GLN2TER
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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">rs104894977 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894977;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=rs104894977" 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=rs104894977" 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=RCV000010407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010407</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><a href="#8" class="mim-tip-reference" title="Brown, S., Yu, C. C., Lanzano, P., Heller, D., Thomas, L., Warburton, D., Kitajewski, J., Stadtmauer, L. <strong>A de novo mutation (gln2stop) at the 5-prime end of the SRY gene leads to sex reversal with partial ovarian function. (Letter)</strong> Am. J. Hum. Genet. 62: 189-192, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9443877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9443877</a>] [<a href="https://doi.org/10.1086/301684" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9443877">Brown et al. (1998)</a> described a 28-year-old West Indian woman with the primary complaint of infertility. She reported menarche and normal breast development at age 13 to 14 years and had had regular monthly menses until age 17 years, when she electively began oral contraceptives, which she continued until age 25 years. Irregular menses resumed with the discontinuation of oral contraception and for the 2 subsequent years she attempted to become pregnant. She had been treated with clomiphene citrate for presumed anovulation. She appeared normally feminized, and her physical examination, including her gynecological examination, was entirely normal, except for the fact that she was 193 cm tall. Specifically, she was not hirsute and had no stigmata of Turner syndrome. Breasts and pubic hair were Tanner stage 4. A chromosome analysis showed a 46,XY karyotype (SRXY1; <a href="/entry/400044">400044</a>). At laparoscopy, the gonads appeared to be white fibrous streaks and were removed without difficulty. Study of all cells failed to detect any with either 2 X chromosomes or without a Y chromosome. The excised gonad from the right side consisted entirely of fibroadipose tissue; the left gonad contained a small amount of ovarian stromal-like tissue. No follicles were seen; however, a cluster of tubular structures was present. Fibroblast-like cells cultured from both gonadal tissue samples also had a pure XY karyotype. Analysis of the SRY gene revealed a C-to-T transition in the second codon, predicted to create a stop codon (gln2ter). The same mutation was found in the gonads of each side. There was no evidence of mosaicism. The patient's father's SRY gene showed an entirely normal sequence. Paternity was proved by the expected segregation of polymorphic PCR-based markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9443877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mouse with a heritable mutation in the testis-determining gene was described by <a href="#50" class="mim-tip-reference" title="Lovell-Badge, R., Robertson, E. <strong>XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy.</strong> Development 109: 635-646, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2401216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2401216</a>] [<a href="https://doi.org/10.1242/dev.109.3.635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2401216">Lovell-Badge and Robertson (1990)</a>. XY mice with this mutation are fertile females, although fertility is reduced and their ovaries fail early, a picture similar to that in the patient reported by <a href="#8" class="mim-tip-reference" title="Brown, S., Yu, C. C., Lanzano, P., Heller, D., Thomas, L., Warburton, D., Kitajewski, J., Stadtmauer, L. <strong>A de novo mutation (gln2stop) at the 5-prime end of the SRY gene leads to sex reversal with partial ovarian function. (Letter)</strong> Am. J. Hum. Genet. 62: 189-192, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9443877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9443877</a>] [<a href="https://doi.org/10.1086/301684" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9443877">Brown et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2401216+9443877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs104894971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894971;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/rs104894971?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=rs104894971" 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=rs104894971" 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=RCV000010408" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010408" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010408</a>
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<p>In 1 of 21 Brazilian patients with 46,XY sex reversal (SRXY1; <a href="/entry/400044">400044</a>), <a href="#17" class="mim-tip-reference" title="Domenice, S., Nishi, M. Y., Billerbeck, A. E. C., Latronico, A. C., Medeiros, M. A., Russell, A. J., Vass, K., Carvalho, F. M., Frade, E. M. C., Arnhold, I. J. P., Mendonca, B. B. <strong>A novel missense mutation (S18N) in the 5-prime non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives.</strong> Hum. Genet. 102: 213-215, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521592</a>] [<a href="https://doi.org/10.1007/s004390050680" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521592">Domenice et al. (1998)</a> found a ser18-to-asn (S18N) missense mutation upstream of the 5-prime border of the HMG box of the SRY gene. The variant sequence was also found in DNA obtained from blood and sperm of his father and in blood cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism. The patient had been evaluated at 4 years of age for ambiguous genitalia, characterized by microphallus, perineal hypospadias, bifid scrotum, and a gonad in the left inguinal region. His basal serum testosterone level was 16 ng/dl rising to 189 ng/dl after hCG stimulation. Histologic study showed a right streak gonad, a left dysgenic testis, and the presence of both wolffian and mullerian ducts. His brother at 18 years of age had normal male external genitalia with complete development of secondary sexual characteristics. The father was a 43-year-old phenotypically normal male. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Canto, P., de la Chesnaye, E., Lopez, M., Cervantes, A., Chavez, B., Vilchis, F., Reyes, E., Ulloa-Aguirre, A., Kofman-Alfaro, S., Mendez, J. P. <strong>A mutation in the 5-prime non-high mobility group box region of the SRY gene in patients with Turner syndrome and Y mosaicism.</strong> J. Clin. Endocr. Metab. 85: 1908-1911, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10843173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10843173</a>] [<a href="https://doi.org/10.1210/jcem.85.5.6609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10843173">Canto et al. (2000)</a> performed molecular studies of the SRY gene in 3 patients with an Ullrich-Turner syndrome (see <a href="/entry/163950">163950</a>) phenotype and bilateral streaks; 2 were 45,X/46,XY mosaic, and the third had a Y marker chromosome. In 2 of the patients, the authors identified an S18N mutation in the 5-prime non-HMG box region in DNA from blood and both streaks. This mutation was not identified in 5 normal males. Sequencing of the DNA region was normal in the father and older brother of patient 1, demonstrating that in this patient the mutation was de novo. The authors concluded that the previous report of a 46,XY patient with partial gonadal dysgenesis and the same mutation indicates the probable existence of a hotspot in this region of the SRY gene and strengthens the possibility that all gonadal dysgeneses constitute a spectrum of the same disorder. They also pointed out that this single genetic abnormality can result in a wide range of phenotypic expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10843173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894972 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894972;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=rs104894972" 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=rs104894972" 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=RCV000010409" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010409" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010409</a>
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<p><a href="#62" class="mim-tip-reference" title="Schaffler, A., Barth, N., Winkler, K., Zietz, B., Rummele, P., Knuchel, R., Scholmerich, J., Palitzsch, K.-D. <strong>Identification of a new missense mutation (gly95glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor.</strong> J. Clin. Endocr. Metab. 85: 2287-2292, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852465</a>] [<a href="https://doi.org/10.1210/jcem.85.6.6637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852465">Schaffler et al. (2000)</a> described a nonmosaic XY sex-reversed female with pure gonadal dysgenesis, including 46,XY karyotype, completely female external genitalia, normal mullerian ducts, absence of wolffian ducts, and streak gonads (SRXY1; <a href="/entry/400044">400044</a>), who harbored a yolk-sac tumor and was referred for the assessment of primary amenorrhea. They identified a novel de novo mutation, a G-to-A transition at position 284 within the HMG box of the SRY gene, resulting in a gly95-to-glu substitution. This mutation was not detected in the patient's father or in her male sibs. The authors concluded that these data provide further evidence to support the functional importance of the putative DNA-binding activity of the SRY HMG box. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894973;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=rs104894973" 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=rs104894973" 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=RCV000010410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010410</a>
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<p><a href="#41" class="mim-tip-reference" title="Jordan, B. K., Jain, M., Natarajan, S., Frasier, S. D., Vilain, E. <strong>Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father.</strong> J. Clin. Endocr. Metab. 87: 3428-3432, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12107262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12107262</a>] [<a href="https://doi.org/10.1210/jcem.87.7.8646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12107262">Jordan et al. (2002)</a> reported an A-to-T transversion at nucleotide 380 (with respect to the initiation codon) in the SRY gene that resulted in a tyr127-to-phe (Y127F) substitution in the protein. This sequence variant was found not only in the XY female patient (SRXY1; <a href="/entry/400044">400044</a>) but also in her father, a phenotypically normal male. However, the Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved TYR residue in the HMG box of SRY. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggested that the variant is a novel mutation with functional consequences. The authors concluded that this allelic SRY variant shared by both an affected female and her normal father emphasizes the importance of modifier genes in the sex determination pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12107262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#Andersson1986" class="mim-tip-reference" title="Andersson, M., Page, D. C., de la Chapelle, A. <strong>Chromosome Y-specific DNA is transferred to the short arm of X chromosome in human XX males.</strong> Science 233: 786-788, 1986.">Andersson et al. (1986)</a>; <a href="#Cherfas1991" class="mim-tip-reference" title="Cherfas, J. <strong>Sex and the single gene.</strong> Science 252: 782, 1991.">Cherfas (1991)</a>; <a href="#Clepet1993" class="mim-tip-reference" title="Clepet, C., Schafer, A. J., Sinclair, A. H., Palmer, M. S., Lovell-Badge, R., Goodfellow, P. N. <strong>The human SRY transcript.</strong> Hum. Molec. Genet. 2: 2007-2012, 1993.">Clepet et al. (1993)</a>; <a href="#Davis1981" class="mim-tip-reference" title="Davis, R. M. <strong>Localisation of male determining factors in man: a thorough review of structural anomalies of the Y chromosome.</strong> J. Med. Genet. 18: 161-195, 1981.">Davis
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(1981)</a>; <a href="#Disteche1986" class="mim-tip-reference" title="Disteche, C. M., Casanova, M., Saal, H., Friedman, C., Sybert, V., Graham, J., Thuline, H., Page, D., Fellous, M. <strong>Small deletions of the short arm of the Y chromosome in 46,XY females.</strong> Proc. Nat. Acad. Sci. 83: 7841-7844, 1986.">Disteche et al. (1986)</a>; <a href="#Evans1979" class="mim-tip-reference" title="Evans, H. J., Buckton, K. E., Spowart, G., Carothers, A. D. <strong>Heteromorphic X chromosomes in 46,XX males: evidence for the involvement of X-Y interchange.</strong> Hum. Genet. 49: 11-31, 1979.">Evans et al. (1979)</a>; <a href="#Ferguson-Smith1966" class="mim-tip-reference" title="Ferguson-Smith, M. A. <strong>X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome.</strong> Lancet 288: 475-476, 1966. Note: Originally Volume II.">Ferguson-Smith
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(1966)</a>; <a href="#Giese1994" class="mim-tip-reference" title="Giese, K., Pagel, J., Grosschedl, R. <strong>Distinct DNA-binding properties of the high mobility group domain of murine and human SRY sex-determining factors.</strong> Proc. Nat. Acad. Sci. 91: 3368-3372, 1994.">Giese et al. (1994)</a>; <a href="#Koopman1991" class="mim-tip-reference" title="Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P., Lovell-Badge, R. <strong>Male development of chromosomally female mice transgenic for Sry.</strong> Nature 351: 117-121, 1991.">Koopman et al. (1991)</a>; <a href="#Koopman1990" class="mim-tip-reference" title="Koopman, P., Munsterberg, A., Capel, B., Vivian, N., Lovell-Badge, R. <strong>Expression of a candidate sex-determining gene during mouse testis differentiation.</strong> Nature 348: 450-452, 1990.">Koopman et al.
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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[<a href="https://doi.org/10.1126/science.3738510" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00005792-199111000-00003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/11981" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301684" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<388::AID-HUMU2>3.0.CO;2-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.85.5.6609" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.2028253" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9378(66)90677-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/364715a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0165-4608(99)00010-2" target="_blank">Full Text</a>]
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Uehara, S., Hashiyada, M., Sato, K., Nata, M., Funato, T., Okamura, K.
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<strong>Complete XY gonadal dysgenesis and aspects of the SRY genotype and gonadal tumor formation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111377</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100380200040" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150734</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050422" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18463302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18463302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18463302[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18463302" 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/10.1101/gr.7101908" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570829</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1570829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Werner, M. H., Huth, J. R., Gronenborn, A. M., Clore, G. M.
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<strong>Molecular basis of human 46X,Y (sic) sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7774012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7774012</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7774012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0092-8674(95)90532-4" target="_blank">Full Text</a>]
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<a id="Whitfield1993" class="mim-anchor"></a>
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Whitfield, L. S., Lovell-Badge, R., Goodfellow, P. N.
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<strong>Rapid sequence evolution of the mammalian sex-determining gene SRY.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8355783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8355783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8355783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/364713a0" target="_blank">Full Text</a>]
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Zeng, Y., Ren, Z., Zhang, M., Huang, Y., Zeng, F., Huang, S.
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<strong>A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8105086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8105086</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8105086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.30.8.655" target="_blank">Full Text</a>]
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Zenteno, J. C., Lopez, M., Vera, C., Mendez, J. P., Kofman-Alfaro, S.
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<strong>Two SRY-negative XX male brothers without genital ambiguity.</strong>
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Hum. Genet. 100: 606-610, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341880</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050561" target="_blank">Full Text</a>]
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Bao Lige - updated : 03/08/2021
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Ada Hamosh - updated : 12/07/2020<br>Patricia A. Hartz - updated : 05/09/2017<br>Ada Hamosh - updated : 12/20/2013<br>Patricia A. Hartz - updated : 5/24/2013<br>Ada Hamosh - updated : 3/9/2010<br>Marla J. F. O'Neill - updated : 10/7/2009<br>Patricia A. Hartz - updated : 9/21/2009<br>Ada Hamosh - updated : 7/11/2008<br>Marla J. F. O'Neill - updated : 1/14/2008<br>John A. Phillips, III - updated : 8/21/2006<br>Marla J. F. O'Neill - updated : 6/20/2005<br>Patricia A. Hartz - updated : 3/10/2005<br>Cassandra L. Kniffin - updated : 11/15/2004<br>Ada Hamosh - updated : 12/1/2003<br>Victor A. McKusick - updated : 7/14/2003<br>John A. Phillips, III - updated : 12/11/2002<br>Victor A. McKusick - updated : 6/19/2002<br>Patricia A. Hartz - updated : 6/18/2002<br>John A. Phillips, III - updated : 2/13/2001<br>Victor A. McKusick - updated : 12/29/1999<br>Ada Hamosh - updated : 8/2/1999<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 3/17/1998<br>Victor A. McKusick - updated : 2/2/1998<br>Victor A. McKusick - updated : 10/7/1997<br>Ada Hamosh - updated : 7/10/1997<br>Victor A. McKusick - updated : 6/18/1997<br>John A. Phillips, III - updated : 4/8/1997<br>Stylianos E. Antonarakis - updated : 7/9/1996<br>Orest Hurko - updated : 2/5/1996
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Victor A. McKusick : 9/22/1992
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alopez : 03/02/2022
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mgross : 06/11/2021<br>mgross : 03/08/2021<br>mgross : 12/07/2020<br>alopez : 05/23/2019<br>alopez : 11/07/2018<br>alopez : 05/09/2017<br>alopez : 05/09/2017<br>alopez : 11/29/2016<br>carol : 07/09/2016<br>alopez : 10/30/2014<br>alopez : 7/30/2014<br>carol : 4/14/2014<br>alopez : 12/20/2013<br>mgross : 5/24/2013<br>terry : 3/28/2013<br>carol : 7/9/2012<br>carol : 6/1/2011<br>alopez : 3/1/2011<br>alopez : 3/9/2010<br>terry : 3/9/2010<br>mgross : 1/25/2010<br>joanna : 1/25/2010<br>wwang : 10/22/2009<br>terry : 10/7/2009<br>carol : 9/22/2009<br>terry : 9/21/2009<br>carol : 8/20/2009<br>terry : 8/18/2009<br>carol : 8/18/2009<br>terry : 3/31/2009<br>alopez : 2/9/2009<br>terry : 9/25/2008<br>alopez : 7/15/2008<br>terry : 7/11/2008<br>wwang : 5/22/2008<br>terry : 5/19/2008<br>carol : 1/18/2008<br>carol : 1/14/2008<br>alopez : 8/21/2006<br>carol : 6/22/2005<br>wwang : 6/20/2005<br>mgross : 3/10/2005<br>ckniffin : 11/15/2004<br>alopez : 12/2/2003<br>terry : 12/1/2003<br>tkritzer : 7/23/2003<br>terry : 7/14/2003<br>alopez : 12/11/2002<br>ckniffin : 8/26/2002<br>cwells : 6/25/2002<br>terry : 6/19/2002<br>carol : 6/18/2002<br>carol : 6/18/2002<br>mgross : 3/5/2001<br>terry : 2/13/2001<br>mcapotos : 1/6/2000<br>terry : 12/29/1999<br>alopez : 8/2/1999<br>terry : 8/2/1999<br>terry : 5/25/1999<br>alopez : 4/1/1998<br>terry : 3/23/1998<br>terry : 3/23/1998<br>alopez : 3/17/1998<br>terry : 3/13/1998<br>mark : 2/3/1998<br>terry : 2/2/1998<br>terry : 2/2/1998<br>mark : 1/13/1998<br>mark : 10/14/1997<br>terry : 10/7/1997<br>mark : 9/1/1997<br>alopez : 8/8/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 6/23/1997<br>jenny : 6/23/1997<br>mark : 6/18/1997<br>jenny : 4/21/1997<br>jenny : 4/8/1997<br>terry : 7/24/1996<br>mark : 7/9/1996<br>mark : 6/11/1996<br>terry : 6/6/1996<br>terry : 4/15/1996<br>mark : 2/5/1996<br>terry : 1/30/1996<br>mark : 12/12/1995<br>pfoster : 11/15/1995<br>mark : 7/20/1995<br>carol : 12/19/1994<br>jason : 7/20/1994<br>warfield : 3/14/1994<br>mimadm : 3/11/1994
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<span class="mim-font">
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<strong>*</strong> 480000
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<h3>
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<span class="mim-font">
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SEX-DETERMINING REGION Y; SRY
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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TESTIS-DETERMINING FACTOR; TDF<br />
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TESTIS-DETERMINING FACTOR ON Y; TDY
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SRY</em></strong>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 763683004;
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<strong>
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<em>
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Cytogenetic location: Yp11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : Y:2,786,855-2,787,682 </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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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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Yp11.2
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<span class="mim-font">
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46XX sex reversal 1
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<span class="mim-font">
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400045
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X-linked dominant
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4
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46XY sex reversal 1
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<span class="mim-font">
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400044
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Y-linked
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>SRY encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA binding proteins.</p>
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<strong>Cloning and Expression</strong>
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<p>Sinclair et al. (1990) identified a gene, which they named SRY (sex-determining region Y), within a 35-kb sex-determining region on the human Y chromosome that was adjacent to the pseudoautosomal boundary. The mouse homolog Sry was subsequently cloned and found to be present in Sxr-prime mice, which have the smallest part of the Y chromosome known to be sex-determining (Gubbay et al., 1990). Furthermore, Sry was deleted from a mutant Y chromosome that was no longer sex-determining (Gubbay et al., 1990). </p><p>Su and Lau (1993) found that the SRY open reading frame encodes a deduced 204-amino acid protein with a calculated molecular mass of 24 kD. There is a DNA-binding HMG motif in the middle of the protein. </p><p>Capel et al. (1993) found that a circular Sry transcript consisting of a single exon represented more than 90% of Sry transcripts in adult mouse testis. In contrast, developing mouse genital ridge exclusively expressed linear Sry transcripts. Circular Sry transcripts were not detected in any other mouse tissue examined and were most likely noncoding. Capel et al. (1993) noted that the human SRY gene is transcribed into a linear form only and lacks the flanking inverted repeats required for circular splicing. </p>
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<strong>Genotype</strong>
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<span class="mim-text-font">
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<p>Goodfellow and Lovell-Badge (1993) provided a major review of SRY and sex determination in mammals. </p><p>From the study of normal males and females, persons with abnormal numbers of sex chromosomes, and persons carrying variant Y chromosomes, a factor (or factors) that determines the differentiation of the indifferent gonads into testes is known to be located on the Y chromosome and specifically on the short arm; this was designated testis-determining factor (TDF) in the 1960s. (See Mendelian Inheritance in Man, 4th ed., figure 1, page lix, 1975.)</p><p>Mittwoch (1992) argued that the 'dogma' that all differences distinguishing male and female mammals can be traced to the presence or absence of a single gene encoding a testis-determining factor lacks, as she said, 'biological validity.' She suggested that the genotype of the functional, i.e., fertile, male differs from that of a functional female by the presence of multiple Y-chromosomal genes in association with but a single X chromosome. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Lahr et al. (1995) used RT-PCR to investigate the transcription of the Sry gene in mice. The gene was transcribed in the hypothalamus, midbrain, and testis of adult male but not adult female mice. Whereas the transcripts in the adult testis were circular, those in brain were linear and therefore capable of translation. Lahr et al. (1995) hypothesized that some male specific properties of the brain may be generated directly by the SRY gene product. </p><p>With use of reporter plasmids, gel shift assays, and transfection experiments, Hossain and Saunders (2001) determined that the product of the WT1 gene (607102) transactivates SRY by binding to its promoter region. They also found that WT1 carrying any of 4 common mutations causing Denys-Drash syndrome failed to activate the SRY promoter. </p><p>Li et al. (2001) found that the R133W SRY mutation (607102.0019), which lies within the HMG DNA-binding domain, had little or no effect on specific DNA binding and bending assays, but resulted in a significant change in cellular location of SRY upon transfection into COS-7 cells and into a male rat gonadal ridge embryogenic cell line. In both model cell systems, wildtype SRY localized to the nuclear compartment, whereas the mutant SRY showed a broad distribution in the cytoplasm and nucleus similar to that observed with deletion of the C-terminal nuclear localization signal (NLS). </p><p>Sekido and Lovell-Badge (2008) demonstrated that Sry binds to multiple elements within a Sox9 (608160) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with steroidogenic factor-1 (SF1) an orphan nuclear receptor encoded by the gene Nr5a1 (184757). Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Sekido and Lovell-Badge (2008) concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal. </p><p>By yeast 2-hybrid screening of a human testis cDNA library, Sato et al. (2011) identified RPS7 (603658) and RPL13A (619225) as SRY-interacting proteins. Pull-down assay confirmed that the HMG box of SRY was required for its interaction with RPS7 and RPL13A. In transiently transfected COS1 cells, SRY, RPS7, and RPL13A colocalized in nuclear speckles. </p><p>Hansen et al. (2013) found that the mouse Sry circular RNA contains 16 putative microRNA-138 (MIR138; see 613394)-binding sites. They showed that Sry bound Mir138 and functioned as an Mir138 sponge, reducing the ability of Mir138 to downregulate expression of a reporter gene. </p><p>Kuroki et al. (2013) found that Jmjd1a (611512) regulates expression of the mammalian Y chromosome Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks. Kuroki et al. (2013) found that Jmjd1a-null mice that were XY were frequently sex reversed, either partially, with a testis and an ovary (12 of 58 animals), or completely, with 2 ovaries (34 of 58 animals). In contrast, all Jmjd1a wildtype and heterozygous XY mice had 2 testes. Kuroki et al. (2013) concluded that their studies revealed a pivotal role of histone demethylation in mammalian sex determination. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</div>
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<span class="mim-text-font">
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<p>Su and Lau (1993) determined that SRY is an intronless gene that spans 3.8 kb. Analysis of the proximal flanking region revealed 2 GC-rich regions containing several Sp1 (189906)-binding sites. The gene also contains a TATAAA motif for the binding of TFIID (TAF5; 601787) and a kappa B enhancer element for the binding of NF-kappa-B (see 164011). </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>TDF was ultimately mapped to the human Y chromosome by molecular examination of sex-reversed patients. Analysis of 4 XX males with testes who had minute portions of the Y material translocated to the X chromosome was critical in defining the sex-determining region on the human Y chromosome (Palmer et al., 1989; Sinclair et al., 1990). The sex-determining region on the human Y chromosome was later defined to a 35-kb region of Y-specific DNA adjacent to the pseudoautosomal boundary (Sinclair et al., 1990). </p><p>Behlke et al. (1993) found that 2 RNAs hybridized to a 4,741-bp genomic segment of the sex-determining region of the human Y chromosome: one transcript deriving from SRY, and a second transcript cross-hybridizing to a pseudogene located 2.5 kb 5-prime of the SRY open reading frame. Analysis of the SRY transcript suggested that the entire SRY protein is encoded by a single exon. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><strong><em>46,XY Complete Gonadal Dysgenesis</em></strong></p><p>
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Jager et al. (1990) analyzed the SRY gene in 12 XY sex-reversed females (400044) and identified a de novo 4-bp deletion (480000.0001) in a conserved DNA-binding motif in 1 patient. </p><p>Hawkins et al. (1992) studied the SRY gene in 5 phenotypic females with complete gonadal dysgenesis and a 46,XY karyotype reported by Berkovitz et al. (1991). They used single-strand conformation polymorphism assay and DNA sequencing to screen the open reading frame and identified mutations in 3 of the 5 patients. Like all the previously described SRY mutations, these mutations--2 point mutations (480000.0006 and 480000.0007) and a single-base deletion (480000.0008)--altered the putative DNA-binding region of the SRY protein. </p><p>Hawkins (1993) performed a mutation analysis of the SRY gene in XY females. He noted that 11 mutations had been described at that time, and all were within the DNA-binding HMG-box region of the protein. </p><p>Cameron and Sinclair (1997) stated that 26 different mutations in the SRY gene have been found in individuals with a 46,XY karyotype. They cited reports stating that no polymorphisms had been described in SRY among 50 normal males. De novo mutations in the SRY HMG-box region almost always resulted in 46,XY unambiguous females with no testicular differentiation. They found 5 reports of familial 46,XY complete gonadal dysgenesis associated with mutations in the SRY HMG-box region. In 4 of these reports, the father carried the same SRY mutation as his 46,XY daughter. None of the mutations appeared to be polymorphisms. Explanations for the sex reversal associated with these familial SRY mutations included paternal gonadal mosaicism for the mutation (yet to be proven) and incomplete penetrance of the mutation. Support for a penetrance effect came from murine studies in which at least 3 autosomal recessive alleles were found to interact with Y-chromosome alleles, resulting in the genesis of XY ovaries and true hermaphrodites (Eicher and Washburn, 1986). Cameron and Sinclair (1997) noted that timing and expression of SRY are exquisitely regulated and probably must reach a threshold. Consequently, a given mutation in SRY against a particular genetic background might produce sufficient SRY expression to reach the threshold required; testis formation can then ensue, accounting for an unaffected father. </p><p>Uehara et al. (2002) found missense mutations in the SRY gene in 2 of 3 patients with the complete form of XY gonadal dysgenesis. Combined with the results of a previous study (Uehara et al., 1999) in which 2 of 3 complete-type patients showed SRY abnormalities, the incidence was estimated at 67%, which is higher than previously thought. A metaanalysis of patients with SRY abnormalities showed an incidence of 52.5% for gonadal tumor formation in patients with SRY abnormalities. Uehara et al. (2002) gave a useful tabulation of the SRY abnormalities that had been described. </p><p>Harley et al. (2003) examined the SRY gene from 4 XY females, each with a missense mutation of a conserved arginine in either 1 of the 2 NLSs of the SRY HMG box. In all cases, mutant SRY protein was partly localized to the cytoplasm, whereas wildtype SRY was strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins and requires cytoplasmic transport factors, whereas the C-terminal NLS is recognized by importin-beta (KPNB1; 602738). The SRY mutant R133W (480000.0019) showed reduced importin-beta binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the 3 other N-terminal NLS mutants examined, 1 unexpectedly showed a marked reduction in importin-beta binding, whereas the other 2 showed normal importin-beta binding, suggesting defects in the importin-independent pathway. Harley et al. (2003) concluded that SRY normally requires the 2 distinct NLS-dependent nuclear import pathways to reach sufficient levels in the nucleus for sex determination. The study documented cases of human disease that were explained, at a molecular level, by the impaired ability of a protein to accumulate in the nucleus. </p><p><strong><em>46,XY True Hermaphroditism</em></strong></p><p>
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Braun et al. (1993) reported a 46,XY true hermaphrodite who had a mutation of SRY in gonadal DNA but not in leukocyte DNA, suggesting that the mutation was postzygotic. Because of this finding, Fuqua et al. (1997) attempted to determine whether postzygotic mutations of SRY might explain the numerous cases of gonadal dysgenesis in which no SRY mutation was detected in leukocyte DNA. They evaluated 16 subjects with 46,XY gonadal dysgenesis who had a normal SRY sequence in leukocyte DNA, 5 of them having 46,XY complete gonadal dysgenesis. They did not find mutations in gonadal DNA from any of 16 subjects and concluded that postzygotic mutations of SRY are a rare cause of 46,XY gonadal dysgenesis. </p><p>Maier et al. (2003) reported a 46,XY true hermaphrodite who had a mutation in the SRY gene (480000.0006). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. Maier et al. (2003) concluded that the mutated protein retained enough activity to allow normal development in some individuals. </p><p><strong><em>46,XX Gonadal Dysgenesis, Complete or Partial</em></strong></p><p>
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Margarit et al. (2000) studied a 46,XX true hermaphrodite and found that Yp-specific sequences, including the SRY gene, had been transferred to the long arm of one of the X chromosomes at the Xq28 level. The derivative X chromosome of the patient lacked q-telomeric sequences. The authors suggested that this was the first report of a Yp/Xq translocation. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences were missing. </p><p>Sharp et al. (2005) studied causes of incomplete masculinization in 15 individuals with segments of Yp translocated onto Xp. Expression studies showed little evidence for the spreading of X inactivation into Yp chromatin; however, in several cases, disruption of gene expression occurred independently of X inactivation, suggesting position effects resulting from chromosomal rearrangement. In particular, 5 of 6 translocation carriers with an intersex phenotype had either translocation breakpoints very close to SRY, or disrupted expression of genes near SRY in a manner unrelated to X inactivation. Southern blot analysis suggested the presence of a cryptic rearrangement 3 to 8 kb proximal to SRY in 1 case. Sharp et al. (2005) suggested that incomplete masculinization in cases of X/Y translocation is a result of disruption of normal SRY expression by position effects rather than X inactivation. </p><p>Zenteno et al. (1997) described a Mexican family in which 2 brothers, aged 28 and 26, were thought to be instances of 'classic' XX males without genital ambiguity but were found to be negative for several Y-chromosome sequences, including SRY. The data suggested that an inherited loss-of-function mutation in a gene participating in the sex-determining cascade can induce normal male sexual differentiation in the absence of SRY. </p><p><strong><em>Mosaicism</em></strong></p><p>
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Shahid et al. (2005) performed molecular genetics studies in 3 Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Two patients carried mutations within the HMG box, and 1 patient carried a frameshift mutation downstream of the HMG box. The authors suggested that lack of a second sex chromosome in a majority of cells (mosaic karyotype and mutation in the SRY gene) in these patients may have triggered the short stature. </p><p>Lange et al. (2009) identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. As expected, the 2 individuals carrying the idicYq chromosomes lacked the SRY gene and were phenotypic females; however, 18 of the 58 idicYp and isoYp individuals, who had 2 copies of SRY, were also 'sex-reversed' and raised as females or found in childhood to have 1 degenerate ovary and 1 testis. Lange et al. (2009) observed that the average intercentromeric distance in the feminized individuals was twice that in the males (p less than 10(-6)), supporting the hypothesis that mitotic instability and resultant XO mosaicism may cause sex reversal. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a human SRY probe, Foster et al. (1992) identified and cloned related genes from the Y chromosome of 2 marsupial species. Comparisons of eutherian ('placental') and metatherian (marsupial) Y-located SRY sequences suggested rapid evolution of these genes, especially outside the region encoding the DNA-binding 'high mobility group' domain (HMG box). The SRY homolog and the homolog of the mouse Ube1y were the first genes to be identified on the marsupial Y chromosome. Whitfield et al. (1993) and Tucker and Lundrigan (1993) likewise found that whereas the central 'high mobility group' domain of about 78 amino acids of the SRY protein is highly conserved, evolution in primates and in mice and rats has been rapid in the regions flanking the conserved domain. The high degree of sequence divergence and the frequency of nonsynonymous mutations suggested either that the majority of the coding sequence has no functional significance and therefore is not functionally constrained or that it has been subject to directional selection with species-specific adaptive divergence. </p><p>Foster and Graves (1994) identified a sequence on the marsupial X chromosome that shares homology with SRY and shows near-identity with the mouse and human SOX3 gene (313430; formerly called a3), the SOX gene most closely related to SRY. Foster and Graves (1994) suggested that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining SRY gene was derived. </p><p>In therian mammals (placentals and marsupials), sex is determined by an XX female:XY male system in which the SRY gene on the Y chromosome affects male determination. Birds have a ZW female:ZZ male system with no homology with mammalian sex chromosomes. In birds, dosage of a Z-borne gene, possibly DMRT1 (602424), affects male determination. Platypus employ a sex-determining system of 5 X and 5 Y chromosomes. Females have 2 copies of the 5 Xs; males have 5X and 5Y chromosomes, which form an alternating XY chain during male meiosis. Veyrunes et al. (2008) found no homology between the 10 platypus sex chromosomes and the ancestral therian X chromosome, which is homologous to platypus chromosome 6. Orthologs of genes in the conserved region of human X (including SOX3, the gene from which SRY evolved) all map to platypus chromosome 6, which therefore represents the ancestral autosome from which the therian X and Y pair derived. The platypus X chromosomes have substantial homology with the bird Z chromosome (including DMRT1), and to segments syntenic with this region in the human genome. Veyrunes et al. (2008) concluded that the therian X and Y chromosomes, including the SRY gene, evolved from an autosomal pair after the divergence of monotremes only 166 million years ago. </p><p>Hughes et al. (2010) finished sequencing the male-specific region of the Y chromosome (MSY) in chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. Comparison of the MSYs of the 2 species showed that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. Hughes et al. (2010) suggested that the extraordinary divergence of the chimpanzee and human MSYs was driven by 4 synergistic factors: the prominent role of the MSY in sperm production, 'genetic hitchhiking' effects in the absence of meiotic crossingover, frequent ectopic recombination within the MSY, and species differences in mating behavior. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The human and mouse Sry genes share 89% amino acid identity in their HMG box domains, but they diverge significantly in their C termini. Coward et al. (1994) found that Sry alleles from all mouse strains examined encode a glutamine- and histidine-rich C-terminal domain. Sry alleles encoding a polyglutamine tract of either 13 or 11 glutamine residues were associated with partial (fetal) or complete sex reversal, respectively, when introduced on a C57BL/6J background. Alleles encoding a tract of 12 glutamine residues were not associated with sex reversal. </p><p>Only the HMG box region of the SRY gene has been conserved through evolution, suggesting that SRY function depends solely on the HMG box and therefore acts as an architectural transcription factor. In mice, SRY includes a large CAG trinucleotide repeat region encoding a C-terminal glutamine-rich domain that acts as a transcriptional trans-activator in vitro. The absence of this or any other potential trans-activating domain in other mammals, however, has raised doubts as to its biologic relevance. To test directly whether the glutamine-rich region is required for SRY function in vivo Bowles et al. (1999) created truncation mutations of the Mus musculus SRY gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay. SRY constructs that encoded proteins lacking a glutamine-rich region were unable to effect male sex determination, in contrast to their wildtype counterparts. Bowles et al. (1999) concluded that the glutamine-rich repeat domain of the mouse SRY protein has an essential role in sex determination in vivo and that SRY may act via a fundamentally different biochemical mechanism in mice compared with other mammals. </p><p>Nef et al. (2003) demonstrated that the insulin receptor tyrosine kinase family, comprising INSR (147670), IGF1R (147370), and IRR (147671), is required for the appearance of male gonads and thus for male sexual differentiation in mice. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry and the early testis-specific marker Sox9 (608160) indicated that the insulin signaling pathway is required for male sex determination. </p><p>In 6 sterile heifers that were female in appearance and in genital organs, Kawakura et al. (1996) found that blood, skin, spleen, and kidney showed a normal male 60,XY karyotype. Although the SRY gene was detected by PCR in normal bull, it was not detected in normal cow or in 3 60,XY female bovine cases studied. </p><p>Using transcription activator-like effector nuclease (TALEN) technology, Kato et al. (2013) created an Sry-knockout XY mouse, which displayed sex reversal. The knockout mice had female external and internal genitalia, wildtype female levels of blood testosterone, and largely female sexually dimorphic nucleus of medial preoptic area of the brain. Mutant mice exhibited a slightly lengthened estrous cycle and performed copulatory behavior as females, although they appeared to be infertile. Ovaries of the mutant mice had fewer developing follicles and were more luteinized that those of wildtype females, which may account for infertility in the Sry-knockout mouse. </p><p>Miyawaki et al. (2020) identified a cryptic second exon in the mouse Sry gene and a corresponding 2-exon Sry transcript that they designated SryT. XY mice lacking SryT only were sex-reversed, and ectopic expression of SryT in XX mice induced male development. SryT mRNA was expressed similarly to that of the canonical single-exon Sry transcript, which the authors called SryS, but the SryT protein was expressed predominantly due to the absence of a degron found at the C terminus of SryS. Sry exon 2 appeared to have evolved recently in mice through acquisition of a retrotransposon-derived coding sequence to replace the degron. Miyawaki et al. (2020) concluded that, in nature, SryT, and not SryS, is the bona fide testis-determining factor in mice. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>DNA-binding proteins are typically involved in the developmental control of gene expression. High mobility group (HMG) proteins contain a DNA-binding motif called the HMG domain. They have been proposed to act either as target-specific transcription factors or as chromatin structure regulatory elements, or both. Jay et al. (1997) stated that more than 100 HMG-box containing proteins have been reported and classified into 2 distinct subgroups according to the sequence specificity of the DNA binding, the number of HMG DNA-binding domains, and phylogenetic considerations. The first subgroup comprises proteins that are all potential transcription factors believed to control gene expression during development. They contain only 1 DNA-binding domain and they bind to DNA in a sequence-specific fashion. The second subgroup consists of all other HMG box-containing proteins, most of which contain more than 1 DNA-binding domain and can bind to DNA in a non-sequence-specific manner. SRY belongs to the first subgroup. Its cloning led to the discovery of a family of both autosomal and X-linked genes called SOX (for 'SRY-box' related) because of the strong homology of their DNA-binding domain with the HMG box of SRY. </p><p>Page et al. (1987) cloned part or all of what they thought to be the TDF gene, found that some sequences were highly conserved in mammals and even birds, and showed that the nucleotide sequence of the conserved DNA codes for zinc finger domains. ZFY (zinc finger protein, Y-linked; 314980) was the designation approved by the HGM workshop committee, with ZFX being the X-linked counterpart. ZFY proved, however, not to be TDF (Palmer et al., 1989). </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>23 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 46,XY SEX REVERSAL 1</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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SRY, 4-BP DEL, NT773
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<br />
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SNP: rs606231178,
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ClinVar: RCV000010390
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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>Jager et al. (1990) demonstrated a mutation in SRY in 1 of 12 sex-reversed XY females with gonadal dysgenesis (SRXY1; 400044) who had no large deletions of the short arm of the Y chromosome. They found a 4-bp deletion (nucleotides 773-776) in the part of the SRY gene that encodes a conserved DNA-binding motif. A frameshift presumably led to a nonfunctional protein. Mutation occurred de novo, because the father had a normal SRY sequence. This provided strong evidence that SRY is TDF. The de novo G-to-A mutation led to a change from methionine to isoleucine. Hawkins (1993) noted that the mutation is in the HMG box of SRY. </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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<h4>
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<span class="mim-font">
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<strong>.0002 REMOVED FROM DATABASE</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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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 46,XY SEX REVERSAL 1</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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SRY, PHE109SER
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<br />
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SNP: rs104894956,
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ClinVar: RCV000010391
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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 XY female with gonadal dysgenesis (SRXY1; 400044), her father, her 2 brothers and an uncle, Jager et al. (1992) found a T-to-C transition in the region of the SRY gene coding for a protein motif known as the high mobility group (HMG) box, a protein domain known to confer DNA-binding specificity on the SRY protein. The mutation resulted in the substitution, at amino acid position 109, of a serine residue for phenylalanine, a conserved aromatic residue in almost all HMG box motifs known. This F109S mutation was not found in 176 male controls. When recombinant wildtype SRY and SRY(F109S) mutant protein were tested in vitro for binding to the target site AAC AAAG, no differences in DNA-binding activity were observed. These results implied that the F109S mutation either is a rare neutral sequence variant, or produces an SRY protein with slightly altered in vivo activity, the resulting sex phenotype depending on the genetic background or environmental factors. The proband had primary amenorrhea and was 180 cm tall. Prior to therapy, mammary development was at stage III (Tanner). No signs of virilization were found. At laparotomy, bilateral streak gonads, atrophic fallopian tubes, and a rudimentary uterus with a narrow lumen were detected. Although the paternal uncle with the F109S mutation had an undescended right testis, the family was unremarkable with regard to infertility, gynecologic tumors, and abnormal sex phenotypes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 46,XY SEX REVERSAL 1</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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SRY, VAL60LEU
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<br />
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SNP: rs104894957,
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ClinVar: RCV000010392, RCV002460889
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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>Vilain et al. (1992) described a family in which all 5 XY individuals in 2 generations had a single basepair substitution resulting in an amino acid change in the conserved domain of the SRY open reading frame. A G-to-C transversion at nucleotide 588 resulted in substitution of leucine for valine-60. Three of the individuals were XY sex-reversed females (SRXY1; 400044) and 2 were XY males. One of the males had 8 children; all were phenotypic females, including 2 who were sex-reversed XY females carrying the mutation mentioned. Several models were proposed to explain association between a sequence variant in SRY and 2 alternative sex phenotypes. These explanations included the existence of alleles at an unlinked locus. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 46,XY SEX REVERSAL 1</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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SRY, GLN93TER
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<br />
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SNP: rs104894958,
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ClinVar: RCV000010393
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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>McElreavey et al. (1992) described an XY sex-reversed female with pure gonadal dysgenesis (SRXY1; 400044) who harbored a de novo nonsense mutation in SRY, which resulted directly in the formation of a stop codon in the putative DNA-binding motif. A C-to-T transition at nucleotide 687 changed a glutamine codon (CAG) to a termination codon (TAG). The patient, referred to by the authors as the 'propositus,' was a phenotypic female who presented at age 20 years for primary amenorrhea. Treatment with estrogen induced menstruation and slight enlargement of the breasts which were underdeveloped. Laparotomy showed 2 streak gonads without germ cells or remnants of tubes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 46,XY SEX REVERSAL 1</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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46,XY TRUE HERMAPHRODITISM, 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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SRY, ILE90MET
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<br />
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SNP: rs104894959,
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gnomAD: rs104894959,
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ClinVar: RCV000010394, RCV000010395
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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 'patient 213' (patient 4 in the report of Berkovitz et al., 1991), a phenotypic female with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; 400044), Hawkins et al. (1992) identified a C-G transversion at nucleotide 680, causing an isoleucine-to-methionine amino acid substitution within the HMG box. The father and brother of patient 213 also carried the mutation, which was not found in 78 ethnically matched unrelated males. The authors noted that in vitro studies by Harley et al. (1992) demonstrated that the I90M mutant had reduced DNA-binding activity. </p><p>Dork et al. (1998) observed this mutation in a patient unrelated to that reported by Hawkins et al. (1992). None of the previously reviewed mutations had been observed in more than a single family. In 3 cases, however, fertile fathers were found to share the same SRY mutation with their sex-reversed daughters (Berta et al., 1990; Jager et al., 1992; Vilain et al., 1992). In the absence of mosaicism, there are plausible explanations for these familiar variants. The variant could fortuitously occur in a family segregating for a different sex-reversing gene, or the variant may predispose toward sex reversal and cause a differentiation effect only in association with other genetic or environmental factors. In the case reported by Hawkins et al. (1992), I90M was likewise associated with complete gonadal dysgenesis in the proband but was also present in normal relatives of the patient, including the father. Thus, Dork et al. (1998) concluded that this appears to be an instance of a Y-linked inherited disorder with incomplete penetrance and suggested that identification of unrelated individuals carrying the I90M mutation may help to elucidate the mechanism. </p><p>Maier et al. (2003) reported a 46,XY true hermaphrodite (see 400044) who had the I90M mutation in the SRY gene. The father, 3 uncles, and an older brother carried the identical mutation without phenotypic effects. Maier et al. (2003) concluded that the mutated protein retained enough activity to allow normal development in some individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 46,XY SEX REVERSAL 1</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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SRY, LYS106ILE
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<br />
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SNP: rs104894964,
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ClinVar: RCV000010396
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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 their 'patient 207' (patient 5 of Berkovitz et al., 1991) with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; 400044), Hawkins et al. (1992) identified an A-T transversion at nucleotide 727, resulting in a lysine-to-isoleucine substitution within the HMG box. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, 1-BP DEL, 734A
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|
|
<br />
|
|
|
|
SNP: rs606231179,
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|
|
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|
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|
|
ClinVar: RCV000010397
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In their 'patient 208' (patient 6 of Berkovitz et al., 1991) with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; 400044), Hawkins et al. (1992) found deletion of nucleotide 734 causing a frameshift. The father and brother of patient 208 did not share the deletion, indicating that the mutation was de novo. Hawkins (1993) noted that the mutation is in the HMG box of SRY. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
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<span class="mim-text-font">
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|
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|
SRY, ALA113THR
|
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|
<br />
|
|
|
|
SNP: rs104894966,
|
|
|
|
|
|
|
|
ClinVar: RCV000010398
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Chinese XY female with gonadal dysgenesis described as Swyer syndrome (SRXY1; 400044), Zeng et al. (1993) described a G-to-A transition in codon 113 resulting in a change from alanine to threonine. This residue lies within the putative DNA binding motif. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, TRP107TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894967,
|
|
|
|
|
|
|
|
ClinVar: RCV000010399
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Iida et al. (1994) identified a single-basepair substitution within the HMG box of the SRY gene in a 28-year-old married Japanese woman with a history of primary amenorrhea and infertility. Physical examination showed an apparently normal female with a weight of 62 kg and a height of 170.5 cm. While the external genitalia were those of a female, they were infantile with no hypertrophy of the clitoris. The vagina was normal and a cervix was present. The uterus was normal in shape and position. Laboratory examination demonstrated that the amenorrhea was due to ovarian failure. There was no elevation of androgen levels. The karyotype was 46,XY (SRXY1; 400044). Both gonads were partially resected because of the risk of malignant development and showed fibroadipose tissue with no malignant cells and no ovarian or testicular components. By single-strand conformation polymorphism analysis followed by direct sequencing, Iida et al. (1994) demonstrated a GGT to GAT substitution in codon 107, counted from the initiation site of the gene, which predicted a change from a tryptophan residue to a termination codon. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, ILE68THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894968,
|
|
|
|
|
|
|
|
ClinVar: RCV000010400
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This mutation, which caused sex reversal in a female patient with a 46,XY karyotype (SRXY1; 400044), was used by Haqq et al. (1994) to demonstrate that the structural interactions of the HMG box with DNA was altered to result in failure to induce transcription of the gene for mullerian inhibiting substance. The normal protein-DNA interaction consists of partial side chain intercalation into a widened minor groove. </p><p>Studying this same mutation, Peters et al. (1995) demonstrated that 2 DNA-binding activities of SRY could be distinguished. The sequence-specific recognition of duplex DNA must be required for male sex determination because it was eliminated by this mutation in the SRY HMG box. However, the sequence-independent binding to the sharp angles of 4-way DNA junctions was not affected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, MET64ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894969,
|
|
|
|
|
|
|
|
ClinVar: RCV000010401
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an XY female (SRXY1; 400044), Berta et al. (1990) identified a G-to-A transition in the SRY gene resulting in a change from methionine-64 to isoleucine. This residue lies within the HMG box. The mutation was presumed to be de novo because it was not found in the patient's father or brother. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, TRP70TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894965,
|
|
|
|
|
|
|
|
ClinVar: RCV000010402
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an XY female (SRXY1; 400044), Hawkins et al. (1992) identified a G-to-A transition at codon 70 of SRY which results in a stop codon at trp70. This residue lies within the HMG box. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0014 MOVED TO 480000.0006</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, LYS92TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894970,
|
|
|
|
|
|
|
|
ClinVar: RCV000010403
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an XY female (SRXY1; 400044), Muller et al. (1992) identified an A-to-T transversion at codon 92 of the SRY gene which results in a stop codon at lys92. This residue lies within the HMG box. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, GLY95ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894974,
|
|
|
|
|
|
|
|
ClinVar: RCV000010404
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an XY female (SRXY1; 400044), Hawkins et al. (1992) identified a G-to-C transversion resulting in a change from glycine-95 to arginine. This residue lies within the HMG box. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0017 MOVED TO 480000.0007</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, TYR4TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894975,
|
|
|
|
|
|
|
|
ClinVar: RCV000010405
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Veitia et al. (1997) reported a T-to-A transversion occurring at nucleotide 12 in the SRY gene, resulting in a premature termination codon prior to the HMG box. This was a de novo substitution in a completely sex-reversed patient (SRXY1; 400044). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, ARG133TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894976,
|
|
|
|
|
|
|
|
ClinVar: RCV000010406
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Veitia et al. (1997) found a de novo recurrence of the C-to-T transition which gave rise to the arg133trp mutation first reported by Affara et al. (1993). Both patients had pure gonadal dysgenesis (SRXY1; 400044). The arg at codon 133 was conserved in the SRY gene of all species studied at that time. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, GLN2TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894977,
|
|
|
|
|
|
|
|
ClinVar: RCV000010407
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Brown et al. (1998) described a 28-year-old West Indian woman with the primary complaint of infertility. She reported menarche and normal breast development at age 13 to 14 years and had had regular monthly menses until age 17 years, when she electively began oral contraceptives, which she continued until age 25 years. Irregular menses resumed with the discontinuation of oral contraception and for the 2 subsequent years she attempted to become pregnant. She had been treated with clomiphene citrate for presumed anovulation. She appeared normally feminized, and her physical examination, including her gynecological examination, was entirely normal, except for the fact that she was 193 cm tall. Specifically, she was not hirsute and had no stigmata of Turner syndrome. Breasts and pubic hair were Tanner stage 4. A chromosome analysis showed a 46,XY karyotype (SRXY1; 400044). At laparoscopy, the gonads appeared to be white fibrous streaks and were removed without difficulty. Study of all cells failed to detect any with either 2 X chromosomes or without a Y chromosome. The excised gonad from the right side consisted entirely of fibroadipose tissue; the left gonad contained a small amount of ovarian stromal-like tissue. No follicles were seen; however, a cluster of tubular structures was present. Fibroblast-like cells cultured from both gonadal tissue samples also had a pure XY karyotype. Analysis of the SRY gene revealed a C-to-T transition in the second codon, predicted to create a stop codon (gln2ter). The same mutation was found in the gonads of each side. There was no evidence of mosaicism. The patient's father's SRY gene showed an entirely normal sequence. Paternity was proved by the expected segregation of polymorphic PCR-based markers. </p><p>A mouse with a heritable mutation in the testis-determining gene was described by Lovell-Badge and Robertson (1990). XY mice with this mutation are fertile females, although fertility is reduced and their ovaries fail early, a picture similar to that in the patient reported by Brown et al. (1998). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, SER18ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894971,
|
|
|
|
|
|
gnomAD: rs104894971,
|
|
|
|
|
|
ClinVar: RCV000010408
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 21 Brazilian patients with 46,XY sex reversal (SRXY1; 400044), Domenice et al. (1998) found a ser18-to-asn (S18N) missense mutation upstream of the 5-prime border of the HMG box of the SRY gene. The variant sequence was also found in DNA obtained from blood and sperm of his father and in blood cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism. The patient had been evaluated at 4 years of age for ambiguous genitalia, characterized by microphallus, perineal hypospadias, bifid scrotum, and a gonad in the left inguinal region. His basal serum testosterone level was 16 ng/dl rising to 189 ng/dl after hCG stimulation. Histologic study showed a right streak gonad, a left dysgenic testis, and the presence of both wolffian and mullerian ducts. His brother at 18 years of age had normal male external genitalia with complete development of secondary sexual characteristics. The father was a 43-year-old phenotypically normal male. </p><p>Canto et al. (2000) performed molecular studies of the SRY gene in 3 patients with an Ullrich-Turner syndrome (see 163950) phenotype and bilateral streaks; 2 were 45,X/46,XY mosaic, and the third had a Y marker chromosome. In 2 of the patients, the authors identified an S18N mutation in the 5-prime non-HMG box region in DNA from blood and both streaks. This mutation was not identified in 5 normal males. Sequencing of the DNA region was normal in the father and older brother of patient 1, demonstrating that in this patient the mutation was de novo. The authors concluded that the previous report of a 46,XY patient with partial gonadal dysgenesis and the same mutation indicates the probable existence of a hotspot in this region of the SRY gene and strengthens the possibility that all gonadal dysgeneses constitute a spectrum of the same disorder. They also pointed out that this single genetic abnormality can result in a wide range of phenotypic expression. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 46,XY SEX REVERSAL 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SRY, GLY95GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894972,
|
|
|
|
|
|
|
|
ClinVar: RCV000010409
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Schaffler et al. (2000) described a nonmosaic XY sex-reversed female with pure gonadal dysgenesis, including 46,XY karyotype, completely female external genitalia, normal mullerian ducts, absence of wolffian ducts, and streak gonads (SRXY1; 400044), who harbored a yolk-sac tumor and was referred for the assessment of primary amenorrhea. They identified a novel de novo mutation, a G-to-A transition at position 284 within the HMG box of the SRY gene, resulting in a gly95-to-glu substitution. This mutation was not detected in the patient's father or in her male sibs. The authors concluded that these data provide further evidence to support the functional importance of the putative DNA-binding activity of the SRY HMG box. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0023 46,XY SEX REVERSAL 1</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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SRY, TYR127PHE
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<br />
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SNP: rs104894973,
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ClinVar: RCV000010410
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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>Jordan et al. (2002) reported an A-to-T transversion at nucleotide 380 (with respect to the initiation codon) in the SRY gene that resulted in a tyr127-to-phe (Y127F) substitution in the protein. This sequence variant was found not only in the XY female patient (SRXY1; 400044) but also in her father, a phenotypically normal male. However, the Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved TYR residue in the HMG box of SRY. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggested that the variant is a novel mutation with functional consequences. The authors concluded that this allelic SRY variant shared by both an affected female and her normal father emphasizes the importance of modifier genes in the sex determination pathway. </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>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Andersson et al. (1986); Cherfas (1991); Clepet et al. (1993); Davis
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(1981); Disteche et al. (1986); Evans et al. (1979); Ferguson-Smith
|
|
(1966); Giese et al. (1994); Koopman et al. (1991); Koopman et al.
|
|
(1990); Schmitt-Ney et al. (1995); Taylor et al. (1966); Werner et
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al. (1995)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Bao Lige - updated : 03/08/2021<br>Ada Hamosh - updated : 12/07/2020<br>Patricia A. Hartz - updated : 05/09/2017<br>Ada Hamosh - updated : 12/20/2013<br>Patricia A. Hartz - updated : 5/24/2013<br>Ada Hamosh - updated : 3/9/2010<br>Marla J. F. O'Neill - updated : 10/7/2009<br>Patricia A. Hartz - updated : 9/21/2009<br>Ada Hamosh - updated : 7/11/2008<br>Marla J. F. O'Neill - updated : 1/14/2008<br>John A. Phillips, III - updated : 8/21/2006<br>Marla J. F. O'Neill - updated : 6/20/2005<br>Patricia A. Hartz - updated : 3/10/2005<br>Cassandra L. Kniffin - updated : 11/15/2004<br>Ada Hamosh - updated : 12/1/2003<br>Victor A. McKusick - updated : 7/14/2003<br>John A. Phillips, III - updated : 12/11/2002<br>Victor A. McKusick - updated : 6/19/2002<br>Patricia A. Hartz - updated : 6/18/2002<br>John A. Phillips, III - updated : 2/13/2001<br>Victor A. McKusick - updated : 12/29/1999<br>Ada Hamosh - updated : 8/2/1999<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 3/17/1998<br>Victor A. McKusick - updated : 2/2/1998<br>Victor A. McKusick - updated : 10/7/1997<br>Ada Hamosh - updated : 7/10/1997<br>Victor A. McKusick - updated : 6/18/1997<br>John A. Phillips, III - updated : 4/8/1997<br>Stylianos E. Antonarakis - updated : 7/9/1996<br>Orest Hurko - updated : 2/5/1996
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<p>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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